Method of treating disease

ABSTRACT

The present disclosure relates to methods for treating a variety of diseases and/or ameliorating pain by administering to the ear canal of a subject a composition.

This application is a continuation-in-part of U.S. patent applicationSer. No. 14/931,581, which is a continuation-in-part of InternationalApplication No. PCT/US2014/036855, filed May 5, 2014, which claimspriority to U.S. Provisional Application Ser. No. 61/819,023, filed May3, 2013; and this application is also a continuation-in-part of U.S.patent application Ser. No. 14/270,238, filed on May 5, 2014, whichclaims benefit and priority to U.S. Provisional Application Ser.61/819,023, filed on May 3, 2013, the contents of each of which arehereby incorporated by reference in their entireties. The specification,figures and complete disclosure of U.S. Provisional Application No.61/819,023, PCT/US2014/036855, U.S. patent application Ser. No.14/270,238 and U.S. patent application Ser. No. 14/931,581 areincorporated herein by specific reference for all purposes.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art as known to those skilled therein as of the date of theinvention described and claimed herein.

This patent disclosure contains material that is subject to copyrightprotection. The copyright owner has no objection to the facsimilereproduction by anyone of the patent document or the patent disclosureas it appears in the U.S. Patent and Trademark Office patent file orrecords, but otherwise reserves any and all copyright rights.

FIELD OF THE INVENTION

The present disclosure relates to methods for treating a variety ofdiseases and/or ameliorating pain by administering to the ear canal of asubject a composition.

BACKGROUND OF THE INVENTION

Sympathetic presynaptic nerve cell bodies are located in the lateralhorn of spinal cord segments T1-L2. Sympathetic postsynaptic cell bodiesare in ganglia, either sympathetic chain ganglia or prevertebralganglia. Sympathetic presynaptic fibers get to the sympathetic chain viawhite rami communicantes and either synapse at the level they enter,ascend or descend to synapse, or leave the sympathetic trunk withoutsynapsing as a splanchnic nerve to go to a prevertebral ganglion.Sympathetic postsynaptic fibers may enter the spinal nerves via grayrami communicantes to be distributed with dorsal and ventral primaryrami, may form perivascular plexuses to be distributed with bloodvessels, or may travel to the target organ directly. The sympatheticnervous system provides sympathetic innervation to essentially everypart of the body.

Parasympathetic presynaptic cell bodies are located in the brainstem andthe lateral horns of spinal cord segments S2, S3, and S4 and leave theCNS in cranial nerves III, VII, IX and X, and in pelvic splanchnicnerves arising from the ventral primary rami of spinal nerves S2, S3,and S4. The parasympathetic postsynaptic cell bodies are located in fourpairs of ganglia in the head (associated with cranial nerves III, VIIand IX), and otherwise in microscopic ganglia either on or in the wallof the target organ. The distribution of the parasympathetic nervoussystem is more limited than the sympathetic nervous system, with cranialnerves III, VII and IX supplying smooth muscle and glands of the head,the vagus nerve supplying the visceral organs up to the left colicflexure, and the pelvic splanchnics supplying the descending and sigmoidcolon, rectum and pelvic viscera. With the exception of the externalgenitalia, the parasympathetic nervous system does not reach the bodywall.

The autonomic nervous system allows vertebrate species to go about theirdaily business without having to think about the mechanics of theirorgans. Hearts beat, intestines digest, blood vessels change diameter,and vertebrates adapt appropriately to any situation, all without ourhaving to think about it.

SUMMARY OF THE INVENTION

The invention provides for methods for treating a variety of diseasesthat comprises performing topical auricular anesthesia of the externalauditory canal for the purposes of anesthetizing cranial nerves 5, 7, 9,10, 11, and 12, along with the parasympathetic nervous system, thesympathetic nervous system. In one embodiment, the invention providesfor auricular anesthesia of the autonomic nervous system. In oneembodiment, auricular anesthesia is performed on the trigeminal nerve,facial nerve, glossopharyngeal nerve, vagus nerve, accessory nerve,hypoglossal nerves, or a combination thereof. The invention furtherprovides for modulation of the general somatic nervous system and thegeneral visceral nervous system by administering an otic pharmaceuticalcomposition comprising one or more anesthetics (such as lidocaine and/ortetracaine) in solution with a pharmaceutical carrier (such as anexcipient) glycerine, and with or without epinephrine. In someembodiments, the otic pharmaceutical composition further comprises ananalgesic, such as a pyrazolone derivative. In some embodiments, thepyrazolone derivative is antipyrene. The invention provides methods fortreating a variety of diseases that comprises performing auricularanesthesia of the sympathetic nervous system via the vagus nerve to thesympathetic plexus. The invention also provides methods for treatingpain from any variety of diseases disclosed herein by performingauricular anesthesia of the vagus nerve directly and the sympatheticnerve indirectly thus blocking general somatic afferent signals andgeneral visceral afferent signals. The invention further providesmethods of blocking pain from a variety of diseases that comprisesperforming auricular anesthesia of the vagus nerve with resultantanesthesia to the thalamic nuclei resulting in modulation of generalvisceral afferent pain and general somatic afferent pain. In variousembodiments, the disease is a neurology-psychiatry-related affliction,an ear-nose-throat (ENT)-related affliction, a GU-related affliction, agastrointestinal (GI)-related affliction, a cardiac-related affliction,a pulmonary-related affliction, or a metabolic-related affliction.

In various embodiments, the present invention provides a safe andnon-invasive procedure, by which to treat a host of human diseases, andtheir symptoms, that are associated with the fifth cranial nerve(trigeminal nerve), the seventh cranial nerve (facial nerve), ninthcranial nerve (glossopharyngeal nerve), and the tenth cranial nerve(vagus nerve). The present disclosure provides a method of disruptingthe normal physiological function of the nerve that does not rely uponan invasive and costly surgical procedure. The disclosed methods areable to “block” the transduction of both afferent and efferent signalsfrom being transmitted via the trigeminal, facial, glossopharyngeal orvagus nerves. Such blockage of the transduction of signals on the nerveis achieved by a topical auricular anesthesia procedure, whereby apharmaceutical composition is administered to the ear canal of asubject. It is the cutaneous auricular anesthesia of those nerves andtheir particular close proximity and relationship to their respectiveganglia that allows for their modulation in function. It is thatmodulation of function which results in the modulation of expression ofspecific disease processes.

In an embodiment, the present disclosure provides a method for treatingsymptoms of a disease, which comprises topically administering to an earcanal of a subject a pharmaceutical composition, comprising: (i) ananalgesic and (ii) an anesthetic. In an embodiment, the analgesic is atleast one pyrazolone derivative selected from the group consisting ofampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone. In apreferred embodiment, the analgesic is antipyrine. In an embodiment, theanesthetic is at least one selected from the group consistingbenzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine,larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine,tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine,etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine,prilocaine, ropivacaine, trimecaine, and pharmaceutically acceptablederivatives thereof. In a preferred embodiment, the anesthetic isbenzocaine.

An aspect of the invention provides for an otic pharmaceuticalcomposition, comprising: (i) at least one analgesic comprising apyrazolone derivative. In other aspects of the invention, the oticpharmaceutical composition further comprises (ii) at least oneanesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃. An aspect ofthe invention further provides an otic pharmaceutical compositioncomprising at least 2 anesthetic compounds having Formula I as describedherein. For example, the otic pharmaceutical composition can comprisethe anesthetics tetracaine

and lidocaine

An aspect of the invention provides for a method for treating orameliorating symptoms in a subject with a disease associated with aparticular cranial nerve, wherein the disease is aneurology-psychiatry-related affliction, an ear-nose-throat(ENT)-related affliction, a GU-related affliction, a gastrointestinal(GI)-related affliction, a cardiac-related affliction, apulmonary-related affliction, or a metabolic-related affliction, themethod comprising administering to an ear canal of a subject in need ofsuch treatment an effective amount of a pharmaceutical composition,comprising: (i) at least one analgesic comprising a pyrazolonederivative, and/or (ii) at least one anesthetic comprising Formula I,and wherein said pharmaceutical composition is administered to the earcanal of the subject in a concentration sufficient to physiologicallyalter the activity of the subject's particular cranial nerve compared tothe physiological activity of that particular cranial nerve in a subjectnot administered the pharmaceutical composition.

An aspect of the invention a method for treating or amelioratingsymptoms in a subject with a disease associated with a particularcranial nerve, wherein the disease is a neurology-psychiatry-relatedaffliction, an ear-nose-throat (ENT)-related affliction, a GU-relatedaffliction, a gastrointestinal (GI)-related affliction, acardiac-related affliction, a pulmonary-related affliction, or ametabolic-related affliction, the method comprising administering to anear canal of a subject in need of such treatment an effective amount ofan otic pharmaceutical composition, wherein the pharmaceuticalcomposition comprises at least 2 anesthetic compounds having Formula Ias described herein. For example, the otic pharmaceutical compositioncan comprise the anesthetics tetracaine

and lidocaine

In one embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄comprises H, NH₂,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃. In oneembodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄comprises H, NH₂, or

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In one embodiment, the analgesic is at least one pyrazolone derivativeselected from the group consisting of ampyrone, dipyrone, antipyrine,aminopyrine, and propyphenazone. In a preferred embodiment, theanalgesic is antipyrine. In one embodiment, the anesthetic comprisesbenzocaine

chloroprocaine

cocaine

cyclomethycaine

dimethocaine

also referred to as larocaine), piperocaine

propoxycaine

procaine

also referred to as novocaine), proparacaine

also referred to as proxymetacaine), tetracaine

also referred to as amethocaine), articaine

bupivacaine

cinchocaine

also referred to as dibucaine), etidocaine

levobupivacaine

lidocaine

also referred to as lignocaine and xylocaine), mepivacaine

prilocaine

ropivacaine

farmocaine

trimecaine

bupivacaine, marcaine, a combination of the anesthetics listed herein,or pharmaceutically acceptable derivatives thereof. In anotherembodiment, the anesthetic is not benzocaine. In one embodiment, theanesthetic is lidocaine. In one embodiment, the anesthetic istetracaine. In one embodiment, the anesthetic is tetracaine andlidocaine. In one embodiment, the anesthetic is lidocaine andbupivacaine.

In one embodiment, the invention is directed to a method for treating orameliorating symptoms in a subject with a disease associated with aparticular cranial nerve where auricular anesthesia is performed on thetrigeminal nerve (cranial nerve 5), the facial nerve (cranial nerve 7),the glossopharyngeal nerve (cranial nerve 9), the vagus nerve (cranialnerve 10), the spinal accessory nerve (cranial nerve 11), thehypoglossal nerve (cranial nerve 12), or a combination thereof.

The diseases that are treatable by the disclosed methodology arenumerous and described herein. Any disease that is associated with anorgan or bodily tissue that is innervated by the particular nerve couldpotentially be treated by the present methods. Particular mention of thefollowing diseases treatable by the present methods is made: asthma,neurogenic cough, globus hystericus, spasmodic dysphonia,gastroesophageal reflux disease, and obesity. The present methods arealso suitable for treating post-tonsillectomy or post-adenoidectomypharyngeal pain, or oropharyngeal pain.

In one embodiment, the disease is a neurology-psychiatry-relatedaffliction, an ear-nose-throat (ENT)-related affliction, a GU-relatedaffliction, a gastrointestinal (GI)-related affliction, acardiac-related affliction, a pulmonary-related affliction, ametabolic-related affliction, an infection-related affliction, askin-related affliction, a cell proliferation-related affliction, and/ora blood flow-related affliction.

In one embodiment, the neurology-psychiatry-related affliction is atleast one selected from the group consisting of: chronic fatiguesyndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panicattack, Post-Traumatic Stress Disorder, Tourette's Syndrome, FocalDystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless LegSyndrome, Dysautonomia, Familial Intentional Tremor, Migraine pain,Autism Spectrum Disorder, Anxiety Headache, sleeplessness, ReticularActivating System (RAS) dysregulation, Multiple Sclerosis, PeripheralNeuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease,General Somatic Afferent Pain, General Visceral, Afferent Pain, opiatewithdrawal, Dysarthria, ADHD, Nonspecific hand tremor, Stuttering,cerebral palsy, Raynaud's Phenomenon, and excessive sweating, reflexsympathetic dystrophy, sensory processing disorder, and decreasedlibido. In one embodiment, the General Somatic Afferent Pain comprisesNeuromuscular Pain of the neck, back, arms, legs, or shoulders; JointPain; Sciatica pain; Arthritis pain; Shingles Pain; Reflex SympatheticDystrophy pain; or a combination thereof. In one embodiment, a symptomof opiate withdrawal comprises Generalized Pain, Muscle Aches, Nausea,vomiting, Sweating, Diarrhea, or a combination thereof.

In one embodiment, the ear-nose-throat (ENT)-related affliction is atleast one selected from the group consisting of: Palatal Myoclonus, PostTonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough,Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis,Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis,Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, ear pain, neck pain,Dry Eye Syndrome, Trigeminal Neuralgia pain, and Temporomandibular JointPain.

In one embodiment, the Gastroenterology/Urology (GU)-related afflictionis at least one selected from the group consisting of: bladder spasm,dysmenorrhea, pelvic pain, Premature Labor, interstitial cystitis,Prostatitis, Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, KidneyPain, enuresis, dysuria, dyspareunia, encopresis, heavy flowmenstruation, frequent urination, Prolonged Vaginal Bleeding, decreasedrenal blood flow, and chronic renal failure.

In one embodiment, the gastrointestinal (GI)-related affliction is atleast one selected from the group consisting of: irritable bowelsyndrome (IBS), ulcerative colitis, acid reflux, Gastritis,Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic, Hepato-RenalSyndrome, Appetite Suppression, Gall Bladder Pain, Chronic constipation,Chronic diarrhea, and Pancreatitis.

In one embodiment, the cardiac-related affliction is at least oneselected from the group consisting of: Paroxysmal (Lone) (Vagal) AtrialFibrillation, Orthostatic (Neurogenic) Hypotension, Reflex AsystolicSyncope, Postural Orthostatic Tachycardia Syndrome (POTS), VasovagalReflex, cardiac surgery derived cough, heart block, Atrial Contractions,Tachycardia, Congestive Heart Failure, premature atrial contraction, andatrial tachycardia.

In one embodiment, the pulmonary-related affliction is at least oneselected from the group consisting of: asthma, chronic obstructivepulmonary disease (COPD), bronchitis, cystic fibrosis, and Bronchospasm.

In one embodiment, the metabolic-related affliction is at least oneselected from the group consisting of: hypertension, diabetes, septicshock, neurogenic shock, hyperglycemia, hypercholesteremia, and insulinresistance.

In one embodiment, the infection-related affliction is at least oneselected from the group consisting of: Herpes Simplex 1 infection,Herpes, Simplex 2 infection, and Varicella Zoster infection.

In one embodiment, the skin-related affliction is at least one selectedfrom the group consisting of: facial flushing, facial blushing, alopeciaareata, atopic dermatitis, chronic eczema, acne vulgaris, oily skin,rosacea, and morgellons disease.

In one embodiment, the cell proliferation-related affliction is at leastone selected from the group consisting of: cancer and mastocytosis.

In one embodiment, the blood flow-related affliction is at least oneselected from the group consisting of erectile dysfunction, open woundhealing, and sickle cell disease.

In yet other embodiments, the diseases treatable by the disclosedmethodology include, but are not limited to: cardiac diseases,paroxysmal (lone) (vagal) atrial fibrillation, reflex systolic syncope,postural orthostatic tachycardia syndrome (POTS), excessive gag reflex,esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain,esophageal neuralgia, gastritis, dyspepsia, gall bladder disease,colecistitis pain, abdominal pain, esophageal motility disorder oresophageal dysmotility, spastic colon, pancreatic pain or spasms,pediatric colic, rectal spasms and pain, bladder spasm (overactivebladder), interstitial cystitis, dysmenorrhea, premature labor, pelvicpain, chronic pelvic pain, chronic prostatitis pain, eclampsia,preeclampsia, HELLP syndrome, cystitis pain, irritable bowel syndrome,Cohn's disease, ulcerative colitis, reflux disease, gastritis,gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic,hepato-renal syndrome, appetite suppression, gall bladder pain,inflammation of the esophagus, inflammation of the stomach, inflammationof the colon, kidney pain (from stone, infection, or tumor), enuresis,dysuria, dyspareunia, encopresis, heavy flow periods, frequenturination, prolonged vaginal bleeding, inhibit erections, prevention ofpremature ejaculation, inhibit excessive sweating, ureteral spasms,menstrual cramps, uterine spasms, ovarian pain and spasms, fallopiantube pain and spasms, pediatric asthma, adult asthma, chronicobstructive pulmonary disease (COPD), bronchial mucus, acute bronchitis,asthmatic bronchitis, chronic bronchitis, bronchospasm, cystic fibrosis,inflammation of the lung, emphysema, pleuritic chest pain, intercostalmuscle pain, nerve pain, bronchospasm secondary to intubation andextubation, angina pectoris, cardiac vagal blockage, vasovagal reflexblockage, bradycardia, hypotension, orthostatic hypotension,hypertension, diabetes, shock, septic shock, reduction of blood sugar,inflammation of the pancreas, syncope secondary to vagal or cardiacreasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin,neuralgia, laryngospasm, acute laryngitis, laryngeal pain, chroniclaryngitis, post extubation and intubation laryngospasms, palatalmyoclonus, post-tonsillectomy pain, snoring, allergic rhinitis,vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis,chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups,rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome,fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panicattacks, post-traumatic stress disorder, Tourette's syndrome, focaldystonia, tic doloreaux, bulimia, anxiety, depression, restless legsyndrome, dysautonomia, familial intentional tremor, migraines, autismspectrum, anxiety headaches, insomnia or sleep disorders, multiplesclerosis, modulation of the reticular activating system, peripheralneuropathy, apraxia, neck and shoulder pain, and Parkinson's disease.

Thus, the present method applies generally to the treatment of anydisease, ailment, or bodily condition that may benefit from the“blockage” of the particular nerve function. That is, any condition thatwould benefit from the hampered ability of the nerve to transmitneurological signals are encompassed by the disclosed method.

In methods disclosed herein, the pharmaceutical composition isadministered to the ear canal of a subject in a concentration sufficientto physiologically alter the activity of the subject's nerve compared tothe physiological activity of a nerve in a subject not administered thepharmaceutical composition. Thus, the present pharmaceutical compositionutilized in a method as disclosed, is able to disrupt the naturalability of the nerve to transmit neurological signals along its length.These signals, both afferent and efferent, are blocked or hampered bythe present methods.

The amount of analgesic present in the pharmaceutical compositioncomprises from about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL, 50 to 100 mg permL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to100 mg per mL, or 100 mg per mL. In some embodiments, the amount ofanalgesic present is from about 50 to 60 mg per mL, or about 54 mg permL, or about 50 to 55 mg per mL, or about 55 to 60 mg per mL.

The amount of anesthetic present in the pharmaceutical compositioncomprises from about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL, 50 to 100 mg permL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to100 mg per mL, or 100 mg per mL. In some embodiments, the amount ofanesthetic present is from about 1 to 20 mg per mL, or about 1 to 15 mgper mL, or about 5 to 15 mg per mL, or about 10 to 20 mg per mL, orabout 10 to 15 mg per mL, or about 14 mg per mL.

The total amount of the pharmaceutical composition administered to apatient during one dosage may comprise from about: 0.001 to 0.01 mL ofsolution, or 0.01 to 0.1 mL of solution, or 0.1 to 0.5 mL of solution,or 0.1 to 1 mL of solution, or 1 to 1.5 mL of solution, or 1.5 to 2 mLof solution, or 2 to 5 mL of solution, or 5 to 10 mL of solution. Theadministration may comprise using a “dropper” bottle that applies“drops” of solution to the patients ear canal during a typical dosage.Such administration may comprise 1 mL 15-20 drops, 0.5 mL 10 drops, 0.25mL 5 drops.

The pharmaceutical composition can comprise at least one anesthetic, atleast one analgesic, or any combination thereof. For example, thecomposition can comprise one anesthetic, such as lidocaine; twoanesthetics, such as lidocaine and bupivacaine; or an anesthetic and ananalgesic, such as benzocaine and antipyrine.

The pharmaceutical composition can be provided in a solution comprising1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, or 95% of one or more anesthetics. In one example, thecomposition comprises 4% lidocaine and 2% bupivacaine.

As used herein, unless otherwise expressly specified, all numbers suchas those expressing values, ranges, amounts, or percentages may be readas if prefaced by the word “about,” even if the term does not expresslyappear. Any numerical range recited herein is intended to include allsub-ranges subsumed therein. Plural encompasses singular and vice versa;e.g., the singular forms “a,” “an,” and “the” include plural referentsunless expressly and unequivocally limited to one referent.

In certain embodiments, the subject treated by the present methods doesnot have an ear infection. Furthermore, in certain embodiments, thesubject treated by the present methods does not have an ear ache or isnot experiencing ear pain.

In particular aspects, the present method is utilized on patients withear infections. That is the present methods in certain embodimentsspecifically are utilized on patients with an external ear canalinfection, with otalgia or with a middle ear infection, associated withor without purulence. Certain embodiments specifically utilize themethods on subjects experience an ear ache or ear pain. In theseembodiments, a first step of method may comprise an ear examination by atreating physician to assure a patient does have an ear infection or isexperiencing ear pain, or has a hole in the eardrum. It may consist ofredness, middle ear effusion or swelling of the tissues of the externalcanal or distortion of the ear drum. In some aspects after ascertainingthat the patient does indeed have an ear infection, whether it is in theear drum, ear canal or middle ear, topical anesthesia in the form ofAntipyrene/benzocaine dissolved in an excipient may be inserted in theear canal in the form of an eardrop to reduce ear pain. This may also bedone with lidocaine and tetracaine in a similar excipient of glycerine,with or without the presence of epinephrine. What is contraindicated isthe usage of any topical anesthetic in the ear canal in the presence ofan ear tube or pressure equalization tube or an active on goingperforation.

The disclosed pharmaceutical compositions utilized in the presentmethods may comprise additional components such as: antibiotics,vasoconstrictors, glycerin, and acetic acid.

The pharmaceutical compositions may comprise any pharmaceuticallyacceptable carrier, or adjuvant, and may be formulated as: solutions,foams, gels, creams, pastes, lotions, emulsions, and combinations of theaforementioned.

The pharmaceutical composition may be administered once a day, twice aday, three times a day, four times a day, five times a day, six times aday, seven times a day, eight times a day, nine times a day, 10 to 20times a day, or up to continuously throughout the day as needed.Further, in certain embodiments, the pharmaceutical composition isadministered upon the onset of an asthma attack. In other embodiments,the pharmaceutical composition is administered upon a person feelinghungry. Some aspects of the methods entail administration of thepharmaceutical composition upon a patient feeling pain in theirpharyngeal region. Certain embodiments contemplate not utilizing thetaught compositions on patients that are experiencing ear pain, or thathave an ear infection, or swelling in the ear associated with an earinfection. In these embodiments, the disclosed method of treatingdiseases associated with the vagus nerve may be immediately halted orstopped upon a patient developing ear pain.

A specifically preferred ailment to be treated by the disclosed methodis the pharyngeal or oropharyngeal pain associated with a post-operativetonsillectomy or a post-operative adenoidectomy. These embodiments treatpain that patients feel after the aforementioned surgical procedures. Inthese embodiments, the pharmaceutical composition is applied to the earcanal of a subject that has had a tonsillectomy or adenoidectomy within:the preceding 168 hours (or 7 days), preceding 48 hours, preceding 24hours, preceding 12 hours, preceding 4 hours, or immediatelypost-operation, prior to administering the pharmaceutical composition.Thus, the present method contemplates doctors prescribing the disclosedprocedure and pharmaceutical composition to patients to utilizeimmediately upon feeling pain in the pharyngeal or oropharyngeal regionspost-surgery.

Another particularly preferred ailment, or disease, to be treated by thedisclosed method is asthma. In certain embodiments, acute asthma attacksare treated by the present methods. These embodiments involveadministering the pharmaceutical composition to the ear canal of asubject that is presently experiencing an acute asthma attack. Further,these embodiments may comprise treatment of a subject that hasexperienced an asthma attack in the last 48, 24, 12, 6, or 1 hours.Thus, the methods taught herein may be used in conjunction with normalbronchodilators and corticosteroids for the treatment and management ofa patient's asthma. The methods may be suitable for use on asthmapatients experiencing a peak expiratory flow rate (PEFR) of 50 to 79% ofthe patient's normal peak flow readings, i.e. “the yellow zone” asclassified by the American Lung Association. The methods are alsosuitable for use on a patient experiencing a peak expiratory flow rateof less than 50% of the patient's normal peak flow reading, i.e. “thered zone.” The methods can be utilized in conjunction with a rescueinhaler when a patient experiences a severe asthma attack. Consequently,in some embodiments, the present pharmaceutical composition is acomponent of a kit, wherein said kit comprises a rescue inhaler and apharmaceutical composition comprising antipyrine and benzocaine. The kitis intended to be kept with a patient that is in danger of suffering asevere asthma attack. Further, in some embodiments, the pharmaceuticalcomposition is part of an emergency first aid kit that is kept in schoolclassrooms, for example. In these embodiments, teachers could utilizethe present pharmaceutical composition in times of emergency, such aswhen a student suffers a severe asthma attack, but yet there is norescue inhaler readily available.

The present methods are also suitable for use in treating chronicasthma. In these embodiments, patients utilize the disclosedcompositions as taught in the present disclosure to prevent the onset ofan acute asthma attack. In these methods, chronic asthma is managed bycontinuous use of the present methods. Thus, in certain embodiments,patients with asthma are administered the pharmaceutical compositionspresented herein before the onset of an asthma attack. For example,certain embodiments of the present methods are effective at controllingasthma in patients that play sports. Often, patients suffering fromasthma will experience a decreased ability to breathe upon physicalexertion, which in some cases may lead to a severe asthma attackrequiring the use of an inhaler. The present methods allow the treatmentof a subject's ear canal with a pharmaceutical composition comprisingantipyrine and benzocaine before the subject engages in playing a sport.In this manner, the present methods may be an effective therapy forpatient's to utilize before engaging in physical activity, in order toreduce the likelihood of having an asthma attack.

Another particularly preferred condition, or disease, to be treated bythe disclosed method is obesity. The present methods treat obesity byproviding a mechanism to suppress a patient's appetite. By suppressing apatient's appetite, the present methods provide another tool fordoctor's to utilize in managing a patient's weight. Thus, obesity may betreated by administering the taught pharmaceutical composition to asubject's ear canal. In some embodiments, subjects are treated with thetaught pharmaceutical composition whenever the subjects experience asensation of hunger. Further, some embodiments administer the disclosedpharmaceutical compositions to the subject's ear canal immediatelybefore a meal is eaten, or 10 minutes to 60 minutes before a meal iseaten, or 20 to 60 minutes before a meal is eaten, or 30 to 60 minutesbefore a meal is eaten, or concurrently with the consumption of a food.Thus, in some aspects, the present method of auricular anesthesia of thevagus nerve is utilized on a patient within an hour prior to the patienteating any food. In this way, the patient's appetite is satiated andless food will be consumed. Further, some embodiments administer thedisclosed pharmaceutical compositions to the subject's ear canal in themorning, preferably before the subject eats breakfast, thus providing aneffective appetite suppressant that lasts until at least lunch.

In some embodiments, the present pharmaceutical compositions andtreatment methodology are part of a comprehensive weight loss programthat involves not only utilization of the pharmaceutical composition tocurb a patient's appetite, but also may include a specific diet andexercise regime.

In some aspects, a person applying the topical pharmaceuticalcomposition to a patient's ear canal should have good light, so as toget a superficial look into the patient's ear, so as to check for anygross obstructions, i.e. wax, skin, infection, purulence, or swelling.The person may gently pull the ear pinna outward and upward, so as tostraighten out the ear canal. Ear drops comprising the taughtpharmaceutical composition that have been previously warmed and arequite viscid should be applied to the posterior or back wall of thelateral ear opening. The drops should be applied very slowly anddeliberately, one drop at a time, allowing for each drop to slowlymigrate down the ear canal. The patient's head should be resting on itsside on a flat soft surface for optimal application. The back wall ofthe canal and eardrum have a large portion of the vagal nerve fibers,and thus pointed application to this area is desired. In some aspects,children under 10 will require 4 to 8 drops per ear, while adults andchildren over 12 usually require 6 to 10 drops for anesthesia. In someembodiments, drops are always followed by a cotton ball in the lateralear canal for about one hour to insure the maintenance of the medicinein the ear canal to provide the required topical anesthesia to the vagusnerve. After an hour the cotton may be removed.

The administration of a pharmaceutical composition to a patient's earcanal for the purpose of auricular anesthesia of the vagus nerve totreat a disease affected by vagus nerve physiological alteration isreferred to in some embodiments as the “Crews Maneuver.” The CrewsManeuver of utilizing the ear canal as a conduit to anesthetizing thevagus nerve does not suffer from the drawbacks present in the art.

Aspects further comprise methods for ameliorating pain in a subject byadministering to an ear canal of the subject afflicted with a distalpain an effective amount of a pharmaceutical composition comprising atleast one anesthetic comprising Formula I described herein. Inembodiments, a distal pain comprises a non-ear pain. The composition canfurther comprises at least one analgesic comprising a pyrazolonederivative. Still further, the pharmaceutical composition can compriseone or more of an antibiotic, a vasoconstrictor, glycerin, epinephrine,or acetic acid. In some embodiments, 2 or more anesthetics comprisingformula I can be administered to a subject in an effective amount of apharmaceutical composition.

In embodiments, the anesthetic can comprises benzocaine, chloroprocaine,cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine,propoxycaine, procaine, novocaine, proparacaine, tetracaine,amethocaine, articaine, bupivacaine, cinchocaine, dibucaine, etidocaine,levobupivacaine, lidocaine, lignocaine, mepivacaine, prilocaine,ropivacaine, farmocaine, trimecaine, marcaine, bupivacaine, or acombination of the anesthetics listed herein.

In embodiments, the pyrazolone derivative is selected from the groupconsisting of ampyrone, dipyrone, antipyrine, aminopyrine, andpropyphenazone.

In embodiments, the amount of anesthetic does not exceed 252 mg/day. Inembodiments, the amount of analgesic administered does not exceed 972mg/day.

In embodiments, the subject does not have an ear infection, ear pain, ora combination thereof.

Non-limiting examples of distal pain (i.e., non-ear pain) comprisepost-tonsillectomy pharyngeal or oropharyngeal pain, post-adenoidectomypharyngeal or oropharyngeal pain, laryngeal pain, migraine pain, anxietyheadaches, peripheral neuropathy, neck and shoulder pain, generalsomatic afferent pain, neuromuscular pain, joint pain, sciatica pain,arthritis pain, shingles pain, reflex sympathetic dystrophy pain,general visceral afferent pain, post tonsillectomy pain, pharyngealpain, laryngeal pain, neck pain, trigeminal neuralgia pain,temporomandibular joint pain, pelvic pain, chronic prostatitis pain,cystitis pain, kidney pain, gastritis pain, gall bladder pain, andpancreatitis pain.

Aspects are still further directed towards a method for treating asubject suffering from an affliction associated with a particularcranial nerve comprising administering to an ear canal of a subject aneffective amount of a pharmaceutical composition comprising at least oneanesthetic described herein. The composition can further comprises atleast one analgesic comprising a pyrazolone derivative. Still further,the pharmaceutical composition can comprise one or more of anantibiotic, a vasoconstrictor, glycerin, epinephrine, or acetic acid.

In embodiments, the affliction comprises those described herein, such asa neurology-psychiatry-related affliction, ear-nose-throat (ENT)-relatedaffliction, Gastroenterology/Urology (GU)-related affliction,gastrointestinal (GI)-related affliction, cardiac-related affliction,pulmonary-related affliction, metabolic-related affliction,infection-related affliction, skin-related affliction, cellproliferation-related affliction, or blood flow-related affliction.

These and other features, aspects, and advantages of embodiments of thepresent disclosure will become better understood with regard to thefollowing description, claims, and accompanying drawings explainedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 is an illustration of the complex anatomy of the vagus nerve. Theauricular branch is noted.

FIG. 2 is an illustration of the complex anatomy of the vagus nerveshowing the innervation of the parasympathetic division on one side ofthe body.

FIG. 3 is an illustration of the anatomy of the facial nerve.

FIG. 4 is an illustration of the anatomy of the trigeminal nerve.

FIG. 5 is an illustration of the anatomy of the glossopharyngeal nerve.

FIG. 6 is an illustration of the glossopharyngeal nerve.

FIG. 7 is an illustration of the interior of a human ear. The ear canalis noted.

FIG. 8 is an illustration of the nerves of the Esophagus.

FIG. 9 is an illustration of cranial nerves C-3, 5, 7, and 10.

FIG. 10 is an illustration of the distribution of the hypoglossal nerve(cranial nerve 12).

FIG. 11 is an illustration of the anatomy of nerve innervations.

FIG. 12 is an illustration of the anatomy of nerve innervations of thesympathetic (red) and parasympathetic (blue) systems.

FIG. 13 is an illustration of the anatomy of nerve innervations of thesympathetic (blue) and parasympathetic (red) systems.

FIG. 14 is an illustration of the anatomy of nerve innervations, andpreganglionic and ganglionic neurons.

FIG. 15 is an illustration of the anatomy of somatic (orange) andvisceral (blue) motor fibers.

FIG. 16 is an illustration of the anatomy of nerve innervations, andpreganglionic and ganglionic neurons.

FIG. 17 is an illustration of the anatomy of nerve innervations.

FIG. 18 is a map of cranial nerves in equines (top), canines (bottom),and felines (continuation page).

FIG. 19 is an illustration of brains of various vertebrate species.

DETAILED DESCRIPTION OF THE INVENTION

Detailed descriptions of one or more preferred embodiments are providedherein. It is to be understood, however, that the present disclosure maybe embodied in various forms. Therefore, specific details disclosedherein are not to be interpreted as limiting, but rather as a basis forthe claims and as a representative basis for teaching one skilled in theart to employ the present disclosure in any appropriate manner.

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effectiveamount” as used herein is an amount of a compound that is sufficient toeffect beneficial or desired results, including clinical results. Assuch, the effective amount may be sufficient, for example, to reduce orameliorate the severity and/or duration of an affliction or condition,or one or more symptoms thereof, prevent the advancement of conditionsrelated to an affliction or condition, prevent the recurrence,development, or onset of one or more symptoms associated with anaffliction or condition, or enhance or otherwise improve theprophylactic or therapeutic effect(s) of another therapy. An effectiveamount also includes the amount of the compound that avoids orsubstantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results may include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminution of extent of disease, a stabilized (i.e., notworsening) state of disease, preventing spread of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

The term “in need thereof” refers to the need for symptomatic orasymptomatic relief from a condition such as, for example, cancer or aneurodegenerative disease. The subject in need thereof may or may not beundergoing treatment for conditions related to, for example, cancer or aneurodegenerative disease.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which a compound is administered. Non-limiting examples of suchpharmaceutical carriers include liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical carriers may also be saline, gum acacia, gelatin,starch paste, talc, keratin, colloidal silica, urea, and the like. Inaddition, auxiliary, stabilizing, thickening, lubricating and coloringagents may be used. Other examples of suitable pharmaceutical carriersare described in Remington: The Science and Practice of Pharmacy,21^(st) Edition (University of the Sciences in Philadelphia, ed.,Lippincott Williams & Wilkins 2005); and Handbook of PharmaceuticalExcipients, 7^(th) Edition (Raymond Rowe et al., ed., PharmaceuticalPress 2012); each hereby incorporated by reference in its entirety.

The terms “animal,” “subject,” and “patient” as used herein includes allmembers of the animal kingdom including, but not limited to, mammals,animals (e.g., cats, dogs, horses, swine, etc.) and humans.

Autonomic Nervous System.

The autonomic nervous system is divided into the sympathetic andparasympathetic components. The sympathetic nervous system prepares thebody for stress and is called the “fight or flight” system. Theparasympathetic system prepares the body for rest and is called the“rest and digest” or “vegetative” system.

The sympathetic nervous system is one of the two main divisions of theautonomic nervous system; the other being the parasympathetic nervoussystem. Sympathetic nervous system can be modulated or significantlyaffected by the usage of auricular anesthesia to the external auditorycanal. Auricular anesthesia to the external auditory canal can modulatethe vagus and glossopharyngeal nerves, which have direct connections tothe sympathetic chain or nervous system (see FIG. 12, FIG. 13; see alsoFIG. 1 and FIG. 5). The primary process of the sympathetic nervoussystem is to stimulate the body's flight or fight response. It ishowever constantly active at a basic level to maintain homeostasis. Itworks as a compliment in intimate conjunction with the parasympatheticnervous system by direct neural communication.

There are two kinds of neurons involved in the transmission of anysignal through the sympathetic nervous system: preganglionic orpost-ganglionic. The shorter preganglionic neurons originate in thethoracolumbar region of the spinal cord (levels T1 to L2 specifically)to travel to a ganglion often one of the paravertebral ganglion wherethey synapse with a postganglionic neuron. From there, the longpost-ganglionic neuron extends across most of the body. The sympatheticnerves arise from near the middle of the spinal cord in theintermediolateral nucleus of the lateral gray column, beginning at thefirst thoracic vertebrae of the vertebral column and are thought toextend to the second or third lumbar vertebrae. Axons of these nervesleave the spinal cord through the anterior root. They pass near thespinal sensory ganglion and they enter the anterior rami of the spinalnerves. However, unlike somatic innervation, they quickly separate outthrough white rami connectors that connect to either the paravertebralor the prevertebral ganglia extending alongside the spinal column.Presynaptic nerves or axons terminating either of the paravertebralganglia or the prevertebral ganglia. In all cases, the axon enters theparavertebral ganglia at the level of its originating spinal nerve.After this it can either synapse in this ganglion, ascend to a moresuperior, or descend to a more inferior paravertebral ganglion andsynapse there, or it can descend to a prevertebral ganglion and synapsethere with the post-synaptic cell. Post-synaptic cell then goes on toinnervate the target and effector, i.e. gland, smooth muscle, etc.Notable exceptions are the routes for innervation of the suprarenaladrenal medulla. In this case, the presynaptic neurons pass through theparavertebral ganglia onto through the prevertebral ganglia and thensynapse directly with the suprarenal tissue. Auricular anesthesia to thevagus nerve can send signals to the paravertebral ganglia and affectneural transmission and thus affect sympathetic outflow to variousorgans, muscles, blood vessels, glands, skin, and nerves thus affectingdisease processes.

The sympathetic nervous system is involved in hundreds of diseaseprocesses including the following: chronic fatigue syndrome,fibromyalgia, post-traumatic stress disorder, restless leg, anxiety,dysautonomia, hand tremors, migraine headaches, and muscle diseases suchas multiple sclerosis, cerebral palsy, and Parkinson disease. Otherdiseases such as peripheral neuropathies, arthritis, reflex sympatheticdystrophy, muscle aches, sweating, orthostatic hypotension, posturalorthostatic tachycardia syndrome, vasovagal reflex, cardiac arrhythmias,hypertension, diabetes, elevated blood sugar, elevated cholesterol,irritable bowel disease, irritable bowel syndrome, chronic constipation,ulcerative colitis, eclampsia, preeclampsia, HELLP syndrome, prematureejaculation, supraventricular tachycardia, and congestive heart failurecan all be affected by an overactive sympathetic nervous system.Modulation of this system can be accomplished by directly modulating theparasympathetic nervous system via the auricular branch of the vagusnerve and the glossopharyngeal nerve and its intimate connections withthe superior cervical sympathetic ganglion with its connections to therest of the sympathetic nervous system, please see pending figures. Itshould also be noted that functions of the sympathetic nervous systemalso include dilation of pupils, increased in drying of the eyes,increased drying of the nose and the mouth, increasing the heart rateand force of contraction, dilation of bronchials, dilation of skeletalmuscles, dilation of blood vessels going to the brain, decreasing bloodflow to the kidney, decreasing blood flow to the gastrointestinal tract,increasing activation of sweat glands inhibiting peristalsis, increasinglevels of renin, increasing levels of cholesterol and triglycerides,increasing levels of blood pressure, and promoting ignition forejaculation.

The present invention provides for a method of treating or amelioratingsymptoms in a subject with a disease associated with a particularcranial nerve, wherein the disease is a neurology-psychiatry-relatedaffliction, an ear-nose-throat (ENT)-related affliction, a GU-relatedaffliction, a gastrointestinal (GI)-related affliction, acardiac-related affliction, a pulmonary-related affliction, or ametabolic-related affliction. In one embodiment, the disease is aneurology-psychiatry-related affliction, an ear-nose-throat(ENT)-related affliction, a GU-related affliction, a gastrointestinal(GI)-related affliction, a cardiac-related affliction, apulmonary-related affliction, or a metabolic-related affliction. In oneembodiment, the neurology-psychiatry-related affliction is at least oneselected from the group consisting of: chronic fatigue syndrome,fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack,Post-Traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, TicDoloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome,Dysautonomia, Familial Intentional Tremor, Migraine pain, AutismSpectrum Disorder, Anxiety Headache, sleeplessness, Reticular ActivatingSystem (RAS) dysregulation, Multiple Sclerosis, Peripheral Neuropathy,Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General SomaticAfferent Pain, General Visceral, Afferent Pain, opiate withdrawal,Dysarthria, ADHD, Nonspecific hand tremor, Stuttering, cerebral palsy,Raynaud's Phenomenon, and excessive sweating. In one embodiment, theGeneral Somatic Afferent Pain comprises Neuromuscular Pain of the neck,back, arms, legs, or shoulders; Joint Pain; Sciatica pain; Arthritispain; Shingles Pain; Reflex Sympathetic Dystrophy pain; or a combinationthereof. In one embodiment, a symptom of opiate withdrawal comprisesGeneralized Pain, Muscle Aches, Nausea, vomiting, Sweating, Diarrhea, ora combination thereof. In one embodiment, the ear-nose-throat(ENT)-related affliction is at least one selected from the groupconsisting of: Palatal Myoclonus, Post Tonsillectomy Pain, PharyngealPain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, SpasmodicDysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic NasalCongestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis,Tinnitus, Dysphagia, ear pain, neck pain, Dry Eye Syndrome, TrigeminalNeuralgia pain, and Temporomandibular Joint Pain. In one embodiment, theGastroenterology/Urology (GU)-related affliction is at least oneselected from the group consisting of: bladder spasm, dysmenorrhea,pelvic pain, Premature Labor, interstitial cystitis, Prostatitis,Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, Kidney Pain,enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation,frequent urination, Prolonged Vaginal Bleeding, and decreased renalblood flow. In one embodiment, the gastrointestinal (GI)-relatedaffliction is at least one selected from the group consisting of:irritable bowel syndrome (MS), ulcerative colitis, acid reflux,Gastritis, Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic,Hepato-Renal Syndrome, Appetite Suppression, Gall Bladder Pain, Chronicconstipation, Chronic diarrhea, and Pancreatitis. In one embodiment, thecardiac-related affliction is at least one selected from the groupconsisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation,Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, PosturalOrthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiacsurgery derived cough, heart block, Atrial Contractions, Tachycardia,and Congestive Heart Failure. In one embodiment, the pulmonary-relatedaffliction is at least one selected from the group consisting of:asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cysticfibrosis, and Bronchospasm. In one embodiment, the metabolic-relatedaffliction is at least one selected from the group consisting of:hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia,and hypercholesteremia.

General visceral and afferent fibers conduct sensory impulses usuallypain and reflex sensations from the viscera, glands, and blood vesselsto the central nervous system. They are considered to be part of thevisceral nervous system not the autonomic nervous system. However,unlike the efferent fibers of the autonomic nervous system the afferentfibers are not classified as either sympathetic or parasympathetic.General visceral afferent create referred pain to activating generalsomatic afferent fibers where the two meet in the posterior horn of thespinal cord. The cranial nerves that contain general visceral afferentfibers include the facial nerve, the glossopharyngeal nerve, and thevagus nerve all of which innervate the external auditory canal. Generalvisceral afferent referred pain can be modulated by auricular anesthesiato these cranial nerves as they provide sensory innervation to specificareas of the external auditory canal. Topical anesthesia to these areascan modulate general visceral afferent signals from the body back to thecentral nervous system.

General somatic afferent fibers (GSA or somatic sensory nerves) afferentfibers arrive from cells in the spinal ganglia and are found in all thespinal nerves, except occasionally the first cervical, and conductimpulses of pain, touch, and temperature from the surface of the bodythrough the posterior roots of the spinal cord and impulses of musclesense, tendon sense, and joint sense from the deeper structures. Generalsomatic afferent fibers travel through the sympathetic chain into thespinal nerve into the dorsal root ganglion into the dorsal root and intothe spinal cord. It can travel up the spinal cord to the central nervoussystem to the thalamic level and then onto the cerebrum where they canbe involved in a reflex arch involving visceral motor and somatic motornerves which also travel from the ventral root back through thesympathetic chain to their respectful organs. FIGS. 12-13. It is notknown at this time whether the modulation of the sympatheticparavertebral and prevertebral nervous system modulates pain at theganglion or at the thalamic level at this time. Without being bound bytheory, general somatic afferent pain and general visceral afferent paincan be modulated through auricular anesthesia topically applied to theexternal canal modulating the vagus nerve and its attachments to thesympathetic nervous system.

Vertebrate anatomy has many common neurologic anatomic and physiologicaspects. There is no reason to preclude the usage of topical anesthesiaor auricular modulation of the external auditory canal for purposes ofmodulating disease via cranial nerves and the sympathetic nervous systemin other vertebrate species namely primates, felines, canines, bovines,and rodent species. Without being bound by theory, other vertebratespecies can also benefit from the treatment of specific cranialnerve-associated diseases by way of auricular modulation of theautonomic nervous system. The method comprises topically administeringto an ear canal of a vertebrate subject a pharmaceutical compositioncomprising: i. an analgesic, and/or ii. an anesthetic to the externalauditory canal.

Cranial Nerves.

The vagus nerve, also known as cranial nerve X, is the tenth of twelvepaired cranial nerves and is the longest of the cranial nerves. Uponleaving the medulla between the medullary pyramid and the inferiorcerebellar peduncle, it extends through the jugular foramen, then passesinto the carotid sheath between the internal carotid artery and theinternal jugular vein down below the head, to the neck, chest andabdomen, where it contributes to the innervation of the viscera. Theanatomy of the vagus nerve is illustrated in FIGS. 1 and 2.

Upon exiting the jugular foramen, the vagus nerve forms the jugularganglion and the ganglion nodosum or the superior and inferior vagalganglion. The jugular ganglion is joined by filaments from the petrousganglion of the glossopharyngeal nerve. The auricular branch of thevagus nerve also has connections from the jugular ganglion of ten andthe petrous ganglion of the glossopharyngeal nerve as it enters themastoid canaliculus from the lateral wall of the jugular fossa. Brushingthe temporal bone, the auricular branch of vagas exits thetympanomastoid fissure and divides into two branches; one joins thepost-auricular nerve and the other is distributed to the skin of theback of the ear and to the posterior external acoustic meatus.

The vagus nerve conveys sensory information about the state of thebody's organs to the central nervous system. Approximately 80% of thenerve fibers in the vagus nerve are afferent, or sensory nerves,communicating the state of the viscera to the brain, while the remaining20% are efferent, or functional nerves.

The vagus nerve is responsible for regulating a host of bodilyfunctions, including, but not limited to, breathing, speech, sweating,facilitating in keeping the larynx open during breathing, monitoring andregulating heartbeat, and digestion of food in the stomach, along with ahost of other physiological functions.

Consequently, manipulation of the vagus nerve and subsequent alterationof its normal physiological function may have profound effects upon awide range of human ailments that are associated with vagus nerveregulation. However, the present procedures available in the art foraltering the function of the vagus nerve are highly invasive. Thesecurrent procedures often rely upon the implantation of artificialmechanical devices into the body of a patient. Besides being highlyinvasive surgical procedures, these methods are very costly.

For instance, the United States Food and Drug Administration approved aprocedure called vagus nerve stimulation (VNS) in the late 1990s for thetreatment of partial onset epilepsy. VNS is performed as a surgicalprocedure to install a pacemaker-like device into a subject sufferingfrom epileptic seizures. The device, implanted inside a patient's neckarea, is used to send mild electrical impulses through the vagus nerve.The device is battery operated, and has an electrical pulse generator.After it is implanted, electrodes with insulated plastic are run intothe vagus nerve from under the skin on the patient's neck. The pulse isset to operate alternately, by turning on every few seconds and thenturning off.

Researchers have also begun to investigate the possibility of utilizingthese pacemaker-like devices in the stomach of obese patients to blockthe function of the vagus nerve, in order to suppress appetite. Again,these procedures are highly invasive and involve the implantation ofartificial devices into the body of a patient.

Some surgeons have even performed vagotomy procedures to treat obesity.In these procedures, the surgeon completely severs a patient's vagusnerve. While these procedures successfully allowed the subjects to loseweight, it is apparent that such an invasive and permanent surgicalprocedure is problematic for many patients.

Cranial nerve seven or the facial nerve is one of the twelve pairedcranial nerves (see FIG. 3). It is so named because its main function isto supply motor innervation to the muscles of the face. Other muscles itinnervates are the platysma, the posterior belly of the digastric, andthe stapedius muscle. The sensory and parasympathetic portion of thefacial nerve travels in the nervus intermedius and supplies thefollowing components: (1) taste to the anterior two-thirds of thetongue; (2) secretory and vasomotor fibers to the lacrimal gland, themucus glands of the nose and sinuses, mouth, and the submandibular andsublingual salivary glands; and (3) cutaneous sensory impulses from theexternal auditory meatus and regions of the back of the ear. It is alsothought that a parasympathetic impulse from the nervus intermedius, tothe sphenopalatine ganglion, to the mucosa and submucosa of the nose andparanasal sinuses determines their venous capacitance and level ofcongestion.

The parasympathetic portion of the seventh cranial nerve takes itsorigin in the nucleus salivatorius in the brain stem and enters theinterior acoustic meatus separate from the motor division of the facialnerve. It combines with the facial nerve proximal to the geniculateganglion. The fibers leave the geniculate ganglion through the greatsuperficial petrosal nerve and are joined by the large deep petrosalnerve to form the vidian nerve, or the nerve of the pterygoid canal,where together they move forward to synapse in the sphenopalatineganglion. There they provide parasympathetic innervation to the eye,nose, sinus, palate, pharynx, and salivary glands. The geniculateganglion receives general somatic afferent fibers from the externalauditory canal via the auricular branch of the vagus nerve and itsconnection to the seventh cranial nerve. General somatic sensoryafferent fibers synapse in the geniculate ganglion.

The trigeminal nerve or the fifth cranial nerve is the fifth of twelvepaired cranial nerves and is the largest of all the cranial nerves (seeFIG. 4). It is the great sensory nerve of the skin of the face, scalp,ear canal, the mucus membranes and other internal structures of thehead. It also has functions as motor innervation to the muscles ofmastication and contains proprioceptive fibers. It further carriessensory innervation from the dura of the brain with its variousbranches. The fifth cranial nerve is quite extensive. The main sensorynucleus extends from the pons to the upper spinal cord. The nucleusreceives its afferent fibers from the semi-lunar ganglion, also known asthe Trigeminal ganglion or the Gasserian ganglion. The Trigeminalganglion contains the cell bodies of the sensory fibers for its threemain divisions. It receives three large sensory division: theophthalmic, maxillary, and mandibular divisions. The sensory root fibersleave the ganglion posteriorly to pass their insertion into the pons.

The glossopharyngeal nerve, also known as the ninth cranial nerve, isthe ninth of twelve paracranial nerves that is known as the tympanicnerve and has both sensory and secretory fibers (see FIGS. 5 and 6). Thenerve is a mixed sensory and motor nerve. The sensory component consistsof somatic afferent fibers supplying sensation to the mucus membranes ofthe pharynx and tonsillar region and back of the tongue. The superficialorigin of the glossopharyngeal nerve from the brain stem is by three orfour rootlets in the groove between the olive and the inferior peduncle.It exits the skull through the jugular foramen and runs anteriorlybetween the internal carotid artery and the internal jugular vein. Uponexiting the jugular foramen, it forms a pair of ganglionic swellings:the superior or jugular ganglion, and the inferior or petrosal ganglion.The ganglion contains cell bodies of the sensory fibers of the nerve.The ninth nerve communicates with the vagus nerve or the tenth cranialnerve, the facial nerve, and the sympathetic ganglion. Theglossopharyngeal nerve has five distinct general functions: (1) motor(special visceral efferent) supplies the stylopharyngeus muscle; (2)visceral motor (general visceral efferent) provides parasympatheticinnervation of the parotid gland; (3) visceral sensory (general visceralafferent) carries visceral sensory information from the carotid sinusand carotid body; (4) general sensory (general somatic efferent)provides general sensory information from the skin of the external ear,internal surface of the tympanic membrane, upper pharynx, and posteriorone-third of the tongue; and (5) special sensory (special afferent)provides taste sensation from the posterior one-third of the tongue,including circumvallate papillae.

The accessory nerve or the spinal accessory nerve is cranial nerve 11.The cranial nerve controls the sternocleidomastoid muscle and thetrapezius muscle. The sternocleidomastoid muscle tilts and rotates thehead while the trapezius muscle has several factors on the scapulaincluding shoulder elevation and abduction of the arm. Range of motionand strength testing in the neck and shoulders can be measured during aneurological exam to assess the function of the spinal accessory nerve.Limited range of motion or poor muscle strength indicate damage to thespinal accessory nerve. This can be the result from a variety of causesof the cranial nerves. The spinal accessory nerve exits the craniumthrough a specialized hole or foramen. The nerve originates in themajority of individuals in the neurons situated in the upper spinalcord. From there, the fibers enter the foramen magnum and course alongthe inner wall of the skull toward the jugular foramen through which itexits the skull with the glossopharyngeal (or 9th cranial nerve) and thevagus nerve (or the 10th cranial nerve) owing to is peculiar course thespinal accessory nerve is notable for being the only cranial nerve toboth enter and exit the skull (FIG. 1, FIG. 2, and FIG. 5). Once thenerve exits the jugular foramen, it crosses the internal jugular veinaround the level of the posterior belly of the digastric muscle. Itcourses on to innervate the trapezius and sternocleidomastoid muscles.Function of the spinal accessory nerve is special visceral efferent orinnervation and function of the motor control of the sternocleidomastoidand trapezius muscle. Abnormalities of the spinal accessory nerve cancause spasm of these two muscles along with fasciculation and weaknessor aberrations in head, neck, shoulder, and arm movements and range ofmotion. The spinal accessory nerve is intimately connected to the vagusnerve that is the superior and inferior ganglion of the vagus nerve.Auricular anesthesia of the vagus nerve directly modulates electricalinput and function of the spinal accessory nerve (see FIG. 5).

The hypoglossal nerve is the 12th cranial nerve, and innervates themuscles of the tongue. The nerve arises along with the other cranialnerves in the brain stem. The nerve exits the skull base in theposterior fossa through the hypoglossal canal. As it exits the skull, itgives off a small meningeal branch and picks up a branch from theanterior ramus of C1. It follows in near proximity to the vagus nerveand the spinal position of the accessory nerve and it follows behind thevagus nerve and passes between the internal carotid artery and theinterior jugular vein lying on the carotid sheath. It passes deep intothe posterior belly of the digastric muscle in the submandibular region.It passes lateral to the hyoglossus muscle in the inferior laryngealnerve to reach and efferently innervate the tongue. It is intimatelyinvolved in speech as it innervates the tongue. It innervates intrinsicand extrinsic muscles of the tongue and is characterized as generalsomatic efferent nerve type. It can be modulated by indirect modulationor anesthesia to the vagus nerve, which directly communicates to thehypoglossal nerve (see FIG. 1 and FIG. 5). The hypoglossal nerve isinvolved in speech, as well as swallowing to clear the mouth of salivaand other involuntary activities completed by the tongue. Most functionsare voluntary. Voluntary functions require conscious thought and nervepathways occur in the corticobulbar region of the spinal cord. Thehypoglossal nucleus is supplied by innervation from the reticularformation by which it is involved in several reflexive or automaticmotions and in aiding unconscious movement required upon engaging inspeech and articulation. Modulation of signals to the hypoglossal nervevia the 10th cranial nerve may have profound effects on the improvementof articulation, speech, swallowing, and posterior fossa headaches.

Thus, there is a great need in the medical community for methods oftreating vagus and other cranial nerve associated diseases that are notdependent upon altering the function of the vagus nerve or other cranialnerves through invasive surgical procedures or artificial devices.Specifically, there is a great need in the art for procedures to alterthe function of the vagus and other cranial nerves that arenon-invasive, safe, effective, and economical

Disrupting Transduction of Neurological Signals Along the CranialNerves.

The present invention provides for methods of treating a variety ofdiseases disclosed herein that comprises performing auricular anesthesia(e.g., topical anesthesia) of the external auditory canal for thepurposes of anesthetizing cranial nerves 5, 7, 9, 10, 11, and/or 12. Thepresent invention also provides for methods of treating a variety ofdiseases disclosed herein that comprises performing auricular anesthesia(e.g., topical anesthesia) of the sympathetic and/or parasympatheticnervous system(s). The present invention further for methods of treatinga variety of diseases disclosed herein that comprises performingauricular anesthesia of general visceral afferent, general somaticafferent, general visceral efferent, and/or general somatic efferentnerves. In some embodiments, auricular anesthesia is performed in avariety of vertebrate species including but not limited to species suchas humans, horses, cows, pigs, dogs, cats, etc. In some embodiments,auricular anesthesia is performed by way of administering a combinationof lidocaine and tetracaine combined in solution with an excipientglycerin with and without the presents of epinephrine. Antipyrine andBenzocaine can also be used in conducting auricular anesthesia of theexternal auditory canal for the purpose of treating diseases (seeExamples herein). Glycerin is a usp based substance of the excipient.Tetracaine may also be administered without epinephrine to obtainsimilar results. Other excipients will also be utilized to carry thetopical anesthetic or topical analgesic. In one embodiment, the presentdisclosure provides a method for treating symptoms of a disease whichcomprises topically administering to an ear canal of a subject apharmaceutical composition comprising of an anesthetic and anotheranesthetic. In some embodiments, an analgesic with an anesthetic mayalso be utilized. This would be a separate eardrop in and of itself. Inone embodiment, the analgesic is antipyrine, but could also consist ofother known analgesics. In an embodiment, the anesthetic is at least oneof a selected group consisting of an amide or an ester compounddiscussed herein.

The tenth cranial nerve (vagus nerve) is associated with numerous bodilyorgans and alteration of its normal physiological function can haveprofound effects on a host of human ailments. That is, by “blocking” or“disrupting” or “numbing” the conduction of neurological signals in theparticular nerve, one is able to influence a host of organs that areinnervated by that nerve. Consequently, blocking the transduction ofsignals transmitted along the nerve, whether those signals are afferentor efferent in nature, will alter the normal physiological response ofvarious organs and tissues. This, in turn, can have profoundimplications for treating a variety of diseases, or ailments that areassociated with human organs and tissues that are innervated by theparticular nerve.

Auricular anesthesia of the cutaneous portion of the seventh cranialnerve (facial nerve) carry signals back to the geniculate ganglion whereparasympathetic fibers and sensory fibers are anesthetized, blocked, orotherwise modulated. Anesthesia of the geniculate ganglion and itsconnection to the Sphenopalatine ganglion serve to modulate or blocktransduction of efferent signals through the facial nerve. This canprofoundly affect disease processes such as, but not limited to,allergic rhinitis, vasomotor rhinitis, inflammatory nasal polyposis,chronic sinusitis, chronic nasal congestion, allergic conjunctivitis,sneezing, and rhinitis in all forms.

The sensory aspect of the fifth cranial nerve (trigeminal nerve) dealswith information from the dura, the mucus membranes of the eyes, themucus membranes of the nose and sinuses, the skin of the externalauditory canal eardrum. Auricular anesthesia of the skin of the earcanal then signals to the trigeminal ganglion via the auriculotemporalbranch of the mandibular division of the trigeminal nerve. Modulation ofafferent signals through the trigeminal ganglion has profound effects onmultiple disease processes. Modulating those afferent signals from thedura, the eye, the nose and sinuses leads to modulation of variousdisease processes. Manipulation of dural signals that pass through theophthalmic, maxillary, and mandibular divisions have profound effects inthe treatments of headaches and migraine headaches. Manipulation ormodulation or blockage of afferent signals from the ophthalmic andmaxillary divisions of the trigeminal nerve will result in modulatedefferent signals from the motor division of the seventh cranial nervethat deal with allergic rhinitis, vasomotor rhinitis, all forms ofrhinitis, inflammatory nasal polyposis, chronic sinusitis, chronic nasalcongestion, allergic conjunctivitis and sneezing.

Auricular anesthesia of the cutaneous portion of the ninth cranial nerve(glossopharyngeal nerve) and its proximity to the petrous ganglion andits connection to the seventh cranial nerve and tenth cranial nerve canhave profound effect on certain disease processes. Because of neuralconnections between the glossopharyngeal nerve and those of the seventhand tenth cranial nerves, disease processes specific to those nerves mayalso be modulated. Diseases specific to the glossopharyngeal nerve thatmay be affected by topical auricular anesthesia include, but are notlimited to, pharyngeal pain, post tonsillectomy pain, sneezing, andparotid salivation.

Thus, several embodiments of the present invention comprise a methodthat blocks the transduction of efferent signals via the vagus,trigeminal, facial, or glossopharyngeal nerves. Another embodiment ofthe disclosure blocks the afferent transduction of signals via thevagus, trigeminal, facial, or glossopharyngeal nerves. The presentdisclosure also provides a methodology by which both the afferent andefferent signal transduction via the vagus, trigeminal, facial, orglossopharyngeal nerves is blocked.

In one embodiment, the invention provides for a method of treating orameliorating symptoms in a subject with a disease associated with aparticular cranial nerve, wherein the disease is aneurology-psychiatry-related affliction, an ear-nose-throat(ENT)-related affliction, a GU-related affliction, a gastrointestinal(GI)-related affliction, a cardiac-related affliction, apulmonary-related affliction, or a metabolic-related affliction, themethod comprising administering to an ear canal of a subject in need ofsuch treatment an effective amount of a pharmaceutical composition,comprising: (i) at least one analgesic comprising a pyrazolonederivative, and (ii) at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃,and wherein said pharmaceutical composition is administered to the earcanal of the subject in a concentration sufficient to physiologicallyalter the activity of the subject's particular cranial nerve compared tothe physiological activity of that particular cranial nerve in a subjectnot administered the pharmaceutical composition. In one embodiment, theparticular cranial nerve is the trigeminal nerve, the facial nerve, theglossopharyngeal nerve, the accessory nerve, the hypoglossal nerve, thevagus nerve, or a combination thereof.

Pharmaceutical Compositions.

The methods of the present disclosure utilize the application of apharmaceutical composition to the ear canal of subject in need of suchtreatment. The ear canal is illustrated in FIG. 7. The pharmaceuticalcompositions comprise an analgesic and an anesthetic, one or moreanalgesics, or one or more anesthetics. For example, the composition cancomprise one anesthetic, such as lidocaine; two anesthetics, such aslidocaine and bupivacaine; or an anesthetic and an analgesic, such asbenzocaine and antipyrine.

The analgesic present in embodiments of the disclosure are pyrazolone(C₃H₄N₂O) derivatives. The molecular structure of 3-pyrazolone is asfollows:

Derivatives of the isomeric form 5-pyrazolone are also encompassed bythe disclosure.

Particular embodiments of the present methods utilize antipyrine as thepyrazolone derivative. Antipyrine (C₁₁H₁₂N₂O) is also referred to asphenazone. The molecular structure of antipyrine is as follows:

In one embodiment, the methods and pharmaceutical compositions compriseat least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In another embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄comprises H, NH₂,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In one embodiment, the anesthetic comprises

or a combination thereof.

In one embodiment, the anesthetic comprises benzocaine

chloroprocaine

cocaine

cyclomethycaine

dimethocaine

also referred to as larocaine), piperocaine

propoxycaine

procaine

also referred to as novocaine), proparacaine

also referred to as proxymetacaine), tetracaine

also referred to as amethocaine), articaine

bupivacaine

cinchocaine

also referred to as dibucaine), etidocaine

levobupivacaine

lidocaine

also referred to as lignocaine and xylocaine), mepivacaine

prilocaine

ropivacaine

farmocaine

trimecaine

a combination of the anesthetics listed herein, or pharmaceuticallyacceptable derivatives thereof. In another embodiment, the anesthetic isnot benzocaine.

In one embodiment, the anesthetic is lidocaine.

In one embodiment, the anesthetic is tetracaine.

In one embodiment, the anesthetic is tetracaine and lidocaine.

In one embodiment, the anesthetic is lidocaine and bupivacaine.

The anesthetic present in some embodiments of the disclosure are esterbased anesthetics. In a particular embodiment, the anesthetic isbenzocaine (C₉H₁₁NO₂), the molecular formula of which is as follows:

In another embodiment, the anesthetic is not benzocaine.

Further embodiments of the method utilize amide based anesthetics.

In a preferred embodiment of the present methods, the disclosedpharmaceutical compositions comprise antipyrine as the analgesic andbenzocaine as the anesthetic.

In some embodiments, the disclosed pharmaceutical compositions compriseantipyrine as the analgesic and tetracaine and/or lidocaine as theanesthetic. In some embodiments, the disclosed pharmaceuticalcompositions comprise tetracaine and lidocaine as the anesthetic.

In one embodiment, the invention is directed to an otic pharmaceuticalcomposition. In various embodiments, the otic pharmaceutical compositioncomprises (i) at least one analgesic comprising a pyrazolone derivative,and/or (ii) at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃, andwherein the analgesic is present in the pharmaceutical composition in aconcentration of from about 50 to about 60 mg per mL, and wherein theanesthetic is present in the pharmaceutical composition in aconcentration of from about 10 to about 20 mg per mL.

In one embodiment, R₁ of Formula I comprises

wherein R₂ comprises H or CH₃; wherein R₃ comprises H; wherein R₄comprises H, NH₂, or

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.

In some embodiments, the otic pharmaceutical composition furthercomprises an antibiotic, a vasoconstrictor, glycerin, epinephrine,acetic acid, or a combination thereof. In some embodiments, theanesthetic comprises lidocaine, tetracaine, benzocaine, or a combinationthereof. In some embodiments, the anesthetic is not benzocaine. Infurther embodiments, the anesthetic comprises lidocaine, tetracaine, ora combination thereof.

In one embodiment, the pyrazolone derivative of the otic pharmaceuticalcomposition comprises ampyrone, dipyrone, antipyrine, aminopyrine, orpropyphenazone. In some embodiments, the analgesic is antipyrine.

The pharmaceutical compositions may be formulated in a host of ways,including, but not limited to, the following: solutions, foams, gels,creams, pastes, lotions, emulsions, and combinations of theaforementioned.

Furthermore, the present disclosure contemplates that active ingredientsof the pharmaceutical composition, such as antipyrine and benzocaine,may be infused into material that is then placed into a patient's earcanal. For instance, cotton gauze material could be composed to containthe present pharmaceutical composition, said gauze providing aconvenient application method by which to expose the ear canal to thepresent pharmaceutical composition.

In one embodiment, an otic pharmaceutical composition is administered toan ear canal of a subject in need of such treatment, wherein the subjectis a vertebrate species that includes but is not limited to a human,horse, cow, pig, dog, cat, etc. In some embodiments, the oticpharmaceutical composition comprises a topical anesthetic alone or incombination with other topical anesthetics with or without analgesics.In one embodiment, the analgesic is antipyrine. In another embodiment,the anesthetic is at least one selected from the group consisting ofbenzocaine, formacaine, cocaine, and cyclomethycaine. In otherembodiments, the anesthetic comprises tetracaine and/or lidocaine. Insome embodiments, the otic pharmaceutical composition further comprisesthe presence or absence of epinephrine, suspended in solution of variouspharmaceutical carriers. The otic pharmaceutical composition issubsequently administered to the ear canal for the desired effect.

Anatomical Site of Application of the Pharmaceutical Composition

The invention provides for methods for treating a variety of diseasesthat comprises performing topical auricular anesthesia of the externalauditory canal for the purposes of anesthetizing cranial nerves 5, 7, 9,10, 11, and 12, along with anesthetizing the parasympathetic nervoussystem, and/or the sympathetic nervous system. In one embodiment, theinvention provides for treating a variety of diseases that comprisesperforming topical auricular anesthesia of the autonomic nervous system.In one embodiment, auricular anesthesia is performed on the trigeminalnerve (cranial nerve 5), the facial nerve (cranial nerve 7), theglossopharyngeal nerve (cranial nerve 9), the vagus nerve (cranial nerve10), the spinal accessory nerve (cranial nerve 11), the hypoglossalnerve (cranial nerve 12), or a combination thereof. The inventionfurther provides for modulation of the general somatic nervous systemand the general visceral nervous system by administering an oticpharmaceutical composition comprising one or more anesthetics (such aslidocaine and/or tetracaine) in solution with a pharmaceutical carrier(such as an excipient) glycerine, and with or without epinephrine. Insome embodiments, the otic pharmaceutical composition further comprisesan analgesic, such as a pyrazolone derivative. In some embodiments, thepyrazolone derivative is antipyrene.

The present method contemplates applying the disclosed pharmaceuticalcomposition to the ear canal of a patient. It has been found that theear canal serves as a convenient point in the human anatomy in which toapply the present pharmaceutical composition and achieve disruption ofneurological signals along the vagus or other cranial nerves. That is,by placing a pharmaceutical composition, as described herein, into theear canal of a patient, it has been discovered that the body will absorbthe composition and the vagus or other cranial nerve will be “blocked,”such that the normal physiological function of the nerve will bealtered. The present methodology of utilizing the ear canal as a conduitto anesthetizing the particular nerve does not suffer from the drawbackspresent in the prior art.

The present methods of applying a pharmaceutical composition asdescribed are not invasive and do not pose the risks associated withsurgical procedures. Furthermore, the present methods do not rely uponinserting artificial devices into the body of patient. It is evidentthat the present methods represent a significant advancement over thestate of the art, as the disclosed non-invasive procedure is able toalter the function of the vagus or other cranial nerve withoutartificial devices or surgery. The present methods are also economicaland would therefore provide access to treatment to the vast majority ofa population.

The presently disclosed embodiments of a method of blocking signaltransduction upon the vagus nerve will now be further elaborated upon byreference to the following examples. In each of these examples, thedisclosed method was able to successfully treat a human disease, orailment, that was associated with a particular cranial nerve. Withoutbeing bound by theory, the methods are also useful to treat a disease orailment associated with a particular cranial nerve in a variety ofvertebrate species including but not limited to horses, cows, pigs,dogs, cats, etc. Conditions treated in the examples disclosed hereinwere able to be controlled to a clinically effective degree by thedisclosed method of performing auricular anesthesia on the vagus orother cranial nerve, or by performing auricular anesthesia of theautonomic nervous system, i.e. referred to as the “Crews Maneuver.” Inone embodiment, the disease is a neurology-psychiatry-relatedaffliction, an ear-nose-throat (ENT)-related affliction, a GU-relatedaffliction, a gastrointestinal (GI)-related affliction, acardiac-related affliction, a pulmonary-related affliction, or ametabolic-related affliction. In one embodiment, theneurology-psychiatry-related affliction is at least one selected fromthe group consisting of: chronic fatigue syndrome, fibromyalgia,epilepsy, Obsessive Compulsive Disorder, panic attack, Post-TraumaticStress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux,Bulimia, Anxiety, Depression, Restless Leg Syndrome, Dysautonomia,Familial Intentional Tremor, Migraine pain, Autism Spectrum Disorder,Anxiety Headache, sleeplessness, Reticular Activating System (RAS)dysregulation, Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neckand Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain,General Visceral, Afferent Pain, opiate withdrawal, Dysarthria, ADHD,Nonspecific hand tremor, Stuttering, cerebral palsy, Raynaud'sPhenomenon, and excessive sweating. In one embodiment, the GeneralSomatic Afferent Pain comprises Neuromuscular Pain of the neck, back,arms, legs, or shoulders; Joint Pain; Sciatica pain; Arthritis pain;Shingles Pain; Reflex Sympathetic Dystrophy pain; or a combinationthereof. In one embodiment, a symptom of opiate withdrawal comprisesGeneralized Pain, Muscle Aches, Nausea, vomiting, Sweating, Diarrhea, ora combination thereof. In one embodiment, the ear-nose-throat(ENT)-related affliction is at least one selected from the groupconsisting of: Palatal Myoclonus, Post Tonsillectomy Pain, PharyngealPain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, SpasmodicDysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic NasalCongestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis,Tinnitus, Dysphagia, ear pain, neck pain, Dry Eye Syndrome, TrigeminalNeuralgia pain, and Temporomandibular Joint Pain. In one embodiment, theGastroenterology/Urology (GU)-related affliction is at least oneselected from the group consisting of: bladder spasm, dysmenorrhea,pelvic pain, Premature Labor, interstitial cystitis, Prostatitis,Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, Kidney Pain,enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation,frequent urination, Prolonged Vaginal Bleeding, and decreased renalblood flow. In one embodiment, the gastrointestinal (GI)-relatedaffliction is at least one selected from the group consisting of:irritable bowel syndrome (MS), ulcerative colitis, acid reflux,Gastritis, Gastroenteritis, Hyperemesis Gravidarum, Pediatric Colic,Hepato-Renal Syndrome, Appetite Suppression, Gall Bladder Pain, Chronicconstipation, Chronic diarrhea, and Pancreatitis. In one embodiment, thecardiac-related affliction is at least one selected from the groupconsisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation,Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, PosturalOrthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiacsurgery derived cough, heart block, Atrial Contractions, Tachycardia,and Congestive Heart Failure. In one embodiment, the pulmonary-relatedaffliction is at least one selected from the group consisting of:asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cysticfibrosis, and Bronchospasm. In one embodiment, the metabolic-relatedaffliction is at least one selected from the group consisting of:hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia,and hypercholesteremia.

***

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Exemplary methods and materialsare described below, although methods and materials similar orequivalent to those described herein can also be used in the practice ortesting of the present invention.

As will be apparent to one of ordinary skill in the art from a readingof this disclosure, the embodiments of the present disclosure can beembodied in forms other than those specifically disclosed above. Theparticular embodiments described herein are, therefore, to be consideredas illustrative and not restrictive. Those skilled in the art willrecognize, or be able to ascertain, using no more than routineexperimentation, numerous equivalents to the specific embodimentsdescribed herein. The scope of the invention is as set forth in theappended claims and equivalents thereof, rather than being limited tothe examples contained in the foregoing description.

All publications and other references mentioned herein are incorporatedby reference in their entirety, as if each individual publication orreference were specifically and individually indicated to beincorporated by reference. Publications and references cited herein arenot admitted to be prior art.

EXAMPLES

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only, since alternativemethods can be utilized to obtain similar results.

Example 1: Treatment of Post-Tonsillectomy Pharyngeal or OropharyngealPain

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering frompost-tonsillectomy pharyngeal, or oropharyngeal pain.

500 patients that had previously undergone a tonsillectomy wereinstructed to utilize six drops of a pharmaceutical compositioncomprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each earthree times per day, for a duration of ten days after the tonsillectomy.

Results

Out of the 500 patients treated, 495 patients reported significantreduction in pharyngeal and/or oropharyngeal pain.

Example 2: Treatment of Post Adenoidectomy Pharyngeal or OropharyngealPain

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering frompost-adenoidectomy pharyngeal, or oropharyngeal pain.

200 patients that had previously undergone an adenoidectomy wereinstructed to utilize six drops of a pharmaceutical compositioncomprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each eartwo times per day, for a duration of seven days after the adenoidectomy.

Results

Out of the 200 patients treated, 200 patients reported significantreduction in pharyngeal and/or oropharyngeal pain.

Example 3: Treatment of Asthma

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromchronic asthma and acute asthmatic attack.

10 patients with asthma were instructed to utilize six drops of apharmaceutical composition comprising antipyrine (≈54.0 mg) andbenzocaine (≈14.0 mg), in each ear in the morning, for two months.

A patient suffering from a severe acute asthma attack was also treatedby immediately filling the patient's ear canal with the aforementionedpharmaceutical composition.

Results

Out of the 10 patients treated, 10 patients reported significantreduction in asthmatic attacks.

Further, the patient suffering from the severe asthma attack experienceda dramatic increase in the amount of oxygen reaching his lungs within 60minutes of the treatment.

Example 4: Treatment of Obesity (i.e. a Method of Appetite Suppression)

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromobesity.

5 overweight patients were instructed to utilize six drops of apharmaceutical composition comprising antipyrine (≈54.0 mg) andbenzocaine (≈14.0 mg), in each ear in the morning, for an indefiniteperiod of time.

Results

Out of the 5 patients treated, all 5 patients reported significantreduction in appetite while utilizing the treatment. The significantreduction in appetite led to weight loss.

Example 5: Treatment of Neurogenic Cough

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromneurogenic cough.

4 patients suffering from neurogenic cough were instructed to utilizesix drops of a pharmaceutical composition comprising antipyrine (≈54.0mg) and benzocaine (≈14.0 mg), in each ear two times per day, for aduration of seven days and then only as needed.

Results

Out of the 4 patients treated, all 4 patients reported significantreduction in cough.

Example 6: Treatment of Globus Hystericus

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromglobus hystericus.

2 patients suffering from globus hystericus were instructed to utilizesix drops of a pharmaceutical composition comprising antipyrine (≈54.0mg) and benzocaine (≈14.0 mg), in each ear one time per day, for anindefinite period of time as needed.

Results

Out of the 2 patients treated, all 2 patients reported significantreduction in throat tightness.

Example 7: Treatment of Spasmodic Dysphonia

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromspasmodic dysphonia.

One (1) patient suffering from spasmodic dysphonia was instructed toutilize six drops of a pharmaceutical composition comprising antipyrinemg) and benzocaine mg), in each ear one time per day, for an indefiniteperiod of time as needed.

Results

The patient reported significant reduction in throat hoarseness andvocal cord spasms almost immediately upon using the treatment.

Example 8: Treatment of Laryngeal Pain

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromlaryngeal pain.

2 patients suffering from laryngeal pain were instructed to utilize sixdrops of a pharmaceutical composition comprising antipyrine mg) andbenzocaine mg), in each ear one time per day, for an indefinite periodof time as needed.

Results

Out of the 2 patients treated, all patients reported significantreduction in laryngeal pain.

Example 9: Treatment of Gastroesophageal Reflux Disease

Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromGastroesophageal Reflux Disease (GERD).

2 patients suffering from GERD were instructed to utilize six drops of apharmaceutical composition comprising antipyrine mg) and benzocaine mg),in each ear one time per day, for an indefinite period of time asneeded.

Results

Out of the 2 patients treated, all 2 patients reported significantreduction in acid reflux and heartburn.

The results from the aforementioned clinical experiments can be foundbelow in Table 1.

TABLE 1 Clinical Experiments Number of % of Subjects Subjects TreatmentExhibiting Exhibiting Number Protocol Clinical Clinical of (1 mL ≈Amount Improve- Improve- Subjects 15-20 of Time ment in ment in DiseaseTreated Treated drops) Treated Symptoms Symptoms Post- 500 6 drops perFor 10 495 99% Tonsillectomy ear 3 times days post Pharyngeal or per dayoperation Oropharyngeal Pain Post- 200 6 drops per For 7 200 100%Adenoidectomy ear 2 times days post Pharyngeal or per day operationOropharyngeal Pain Asthma 10 6 drops per For 2 10 100% ear in the monthsmorning Obesity via 5 6 drops per Daily 5 100% Appetite ear in theSuppression morning Neurogenic 4 6 drops per 7 days 4 100% Cough ear 2times and then per day as needed Globus 2 6 drops per As 2 100%Hystericus ear once a needed day Spasmodic 1 6 drops per As 1 100%Dysphonia ear once a needed day Laryngeal Pain 2 6 drops per As 2 100%ear once a needed day Gastro- 2 6 drops per As 2 100% esophageal earonce a needed Reflux Disease day (GERD)

Example 10: Treatment of Diseases

Protocol

A test of an embodiment of the present method was conducted to evaluatethe efficacy of the method for treating patients suffering from adisease associated with a particular cranial nerve, wherein the diseaseis a neurology-psychiatry-related affliction, an ear-nose-throat(ENT)-related affliction, a Gastroenterology/Urology (GU)-relatedaffliction, a gastrointestinal (GI)-related affliction, acardiac-related affliction, a pulmonary-related affliction, or ametabolic-related affliction.

Patients suffering from a neurology-psychiatry-related affliction, anear-nose-throat (ENT)-related affliction, a GU-related affliction, agastrointestinal (GI)-related affliction, a cardiac-related affliction,a pulmonary-related affliction, or a metabolic-related affliction wereinstructed to utilize drops of a pharmaceutical composition comprisingantipyrine (≈54.0 mg) and benzocaine (≈14.0 mg) (treatment protocol,“AB” Tmt Protocol) or drops of a pharmaceutical composition comprisinglidocaine (≈40.0 mg) and tetracaine (≈5.0 mg) (treatment protocol, “LAT”Tmt Protocol), in one or both ears, at least one time per day (forexample, either in the morning or at night), for a period of time asneeded (Tmt Time). The LAT otic solution used in the tests comprises 4%Lidocaine, 0.5% Tetracaine, 1/100,000 Epinephrine, and AnhydrousGlycerine. The AB otic solution used in the tests comprises 5.4%Antipyrine, 1.4% Benzocaine, Oxyquinoline Sulfate, and AnhydrousGlycerine.

TABLE 2 Clinical Experiments with Neurology-psychiatry-relatedafflictions Tmt # of Subjects Neurology- Protocol Exhibiting psychiatry-# of (1 mL ≈ Clinical related Subjects 15-20 Tmt Improvement Improvementin affliction Treated drops) Time in Symptoms Symptoms reported Chronic5 LAT: 6 as 4 More energy Fatigue drops per needed More activitySyndrome ear 1x/day Less fatigue 3 AB: 6 4 wks 2 Less muscle and jointdrops per pain ear 1x/day 70% reduction in symptoms w/both tmtsFibromyalgia 5 LAT: 6 4 wks 4 Less muscle and joint (chronic) drops perpain ear 1x/day w/both tmts 3 AB: 6 4 wks 2 drops per ear 1x/dayEpilepsy 1 LAT: 6 4 wks 1 less seizures by 90% (Absence drops per w/bothtmts Seizures) ear 1x/day 2 AB: 6 4 wks 1 drops per ear 1x/day Obsessive3 LAT: 6 4 wks 3 less repetitive behavior Compulsive drops per lessvomiting in Disorder ear 1x/day bulimics Panic Attacks 4 LAT: 6 4 wks 275% less panic attacks drops per w/both tmts ear 1x/day 4 AB: 6 4 wks 2drops per ear 1x/day Post-Traumatic 1 LAT: 6 4 wks 1 Better sleep StressDisorder drops per Less anxiety ear 1x/day Less nightmares 1 AB: 6 4 wks1 Decrease in startle drops per reflex by >50% ear 1x/day w/both tmtsTourette's 1 LAT: 6 4 wks 1 decreased tic activity Syndrome drops perand movement ear 1x/day Focal Dystonia 1 LAT: 6 4 wks 1 50% less eyeblinking drops per w/both tmts ear 1x/day 1 AB: 6 4 wks 1 drops per ear1x/day Anxiety 5 LAT: 6 4 wks 4 70% reduction in drops per nervousnessear 1x/day less need for anxiolytics 3 AB: 6 4 wks 2 w/both tmts dropsper ear 1x/day Depression 5 LAT: 6 4 wks 4 Less depression drops perLess fatigue ear 1x/day 70% increase in activity 3 AB: 6 4 wks 2 w/bothtmts drops per ear 1x/day Restless Leg 5 LAT: 6 4 wks 4 ≥70% reductionin leg Syndrome drops per movements ear 1x/day w/both tmts 3 AB: 6 4 wks2 drops per ear 1x/day Dysautonomia 5 LAT: 6 4 wks 4 ≥70% reduction indrops per parasympathetic and ear 1x/day sympathetic symptoms 3 AB: 6 4wks 2 w/both tmts drops per ear 1x/day Familial 5 LAT: 6 4 wks 5 ≥70%reduction in hand Tremor drops per shaking/tremor ear 1x/day w/both tmts2 AB: 6 4 wks 1 drops per ear 1x/day Migraine pain 5 LAT: 6 4 wks 4 ≥70%reduction in drops per migraine headaches per ear 1x/day month(frequency, 3 AB: 6 4 wks 2 duration, and intensity) drops per w/bothtmts ear 1x/day Autism 5 LAT: 6 4 wks 5 Less outbursts spectrum dropsper Calmer disorder ear 1x/day Better speech 3 AB: 6 4 wks 1 Morefocused drops per w/both tmts ear 1x/day Anxiety 5 LAT: 6 4 wks 5 ≥75%reduction in Headaches drops per headaches per month ear 1x/day(frequency, duration, 5 AB: 6 4 wks 2 and intensity) drops per w/bothtmts ear 1x/day Sleeplessness 5 LAT: 6 4 wks 4 better and continuousdrops per sleep ear 1x/day Multiple 1 LAT: 6 4 wks 1 ≥50% reduction inSclerosis drops per muscle pain ear 1x/day more muscle strength 1 AB: 64 wks 1 w/both tmts drops per ear 1x/day Peripheral 5 LAT: 6 4 wks 4≥50% reduction in Neuropathy drops per peripheral pain ear 1x/day w/bothtmts 5 AB: 6 4 wks 4 drops per ear 1x/day Apraxia 2 LAT: 6 4 wks 2 50%better speech as drops per noted by parents (better ear 1x/day wordpronunciation) 2 AB: 6 4 wks 1 w/both tmts drops per ear 1x/day Neck and5 LAT: 6 4 wks 5 ≥50% reduction in Shoulder Pain drops per pain ear1x/day w/both tmts 3 AB: 6 4 wks 2 drops per ear 1x/day Parkinson's 2LAT: 6 4 wks 2 Less tremors and pain Disease drops per Better Balanceear 1x/day w/both tmts 1 AB: 6 4 wks 1 drops per ear 1x/day General 4LAT: 6 4 wks 3 less neck, back, arm, Somatic drops per leg, shoulder,and chest Afferent Pain- ear 1x/day pain Neuromuscular 2 AB: 6 4 wks 1w/both tmts Pain drops per ear 1x/day General 4 LAT: 6 4 wks 3 ≥50%reduction in pain Somatic drops per requiring less pain Afferent Pain-ear 1x/day medications Joint Pain 3 AB: 6 4 wks 2 w/both tmts(nonspecific) drops per ear 1x/day General 4 LAT: 6 4 wks 3 reduction inpain Somatic drops per Afferent Pain- ear 1x/day Sciatica pain General 4LAT: 6 4 wks 3 reduction in pain Somatic drops per Afferent Pain- ear1x/day Arthritis pain General 4 LAT: 6 4 wks 3 reduction in pain Somaticdrops per Afferent Pain- ear 1x/day Shingles Pain General 3 LAT: 6 4 wks3 ≥70% reduction in Somatic drops per peripheral pain signals AfferentPain- ear 1x/day less electrical, sharp pain Reflex 1 AB: 6 4 wks 1w/both tmts Sympathetic drops per Dystrophy pain ear 1x/day General 5LAT: 6 4 wks 4 ≥70% reduction in Visceral drops per esophageal, stomach,Afferent Pain ear 1x/day intestinal, bladder, and 1 AB: 6 4 wks 1 pelvicpain drops per w/both tmts ear 1x/day Opiate 5 LAT: 6 4 wks 3 Reductionof Muscle Withdrawal drops per aches, back pains, ear 1x/day Nausea,Vomiting, 5 AB: 6 4 wks 3 sweating, diarrhea drops per w/both tmts ear1x/day Dysarthria 5 LAT: 6 4 wks 3 50% better intelligible drops perspeech ear 1x/day w/both tmts 1 AB: 6 4 wks 1 drops per ear 1x/dayAttention 5 LAT: 6 4 wks 4 Calmer Deficit drops per More focusedHyperactivity ear 1x/day Less frequent long- Disorder 3 AB: 6 4 wks 2lasting emotional (ADHD) drops per outbursts ear 1x/day w/both tmtsNonspecific 4 LAT: 6 4 wks 4 50% less tremors hand tremors drops perw/both tmts ear 1x/day 2 AB: 6 4 wks 2 drops per ear 1x/day Stuttering 2LAT: 6 4 wks 2 50% less stuttering drops per w/both tmts ear 1x/day 2AB: 6 4 wks 2 drops per ear 1x/day Cerebral Palsy 1 LAT: 6 4 wks 1Neuromuscular drops per modulation enhanced ear 1x/day better balance 1AB: 6 4 wks 1 walks straighter drops per speech more intelligible ear1x/day w/both tmts Raynaud's 2 LAT: 6 4 wks 2 Better circulationPhenomenon drops per 50% less discoloration ear 1x/day 50% less cyanosis1 AB: 6 4 wks 1 Better warmth to hand drops per w/both tmts ear 1x/dayExcessive 3 LAT: 6 4 wks 2 ≥70% reduction in Sweating drops perperspiration ear 1x/day w/both tmts 2 AB: 6 4 wks 1 drops per ear 1x/day

TABLE 3 Clinical Experiments with ear-nose-throat (ENT)-relatedafflictions. Tmt # of Subjects Protocol Exhibiting % of Subjects # of (1mL ≈ Clinical Exhibiting Clinical ENT-related Subjects 15-20 TmtImprovement Improvement in affliction Treated drops) Time in SymptomsSymptoms Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50% reduction in Paindrops per pain ear 1x/day Reduction of pain 50 AB: 6 4 wks 50medications drops per w/both tmts ear 1x/day Pharyngeal Pain 50 LAT: 6 4wks 50 ≥70% reduction in drops per throat pain ear 1x/day w/both tmts 50AB: 6 4 wks 50 drops per ear 1x/day Laryngeal Pain 5 LAT: 6 4 wks 5 ≥50%reduction in drops per laryngeal pain ear 1x/day w/both tmts 5 AB: 6 4wks 5 drops per ear 1x/day Neurogenic Cough 5 LAT: 6 4 wks 5 ≥70%reduction in drops per cough ear 1x/day w/both tmts 5 AB: 6 4 wks 5drops per ear 1x/day Globus Hystericus 5 LAT: 6 4 wks 5 ≥70% reductionin drops per tightness of throat ear 1x/day fullness 2 AB: 6 4 wks 2w/both tmts drops per ear 1x/day Spasmodic 5 LAT: 6 4 wks 4 ≥70%reduction in Dysphonia drops per dysphonia ear 1x/day w/both tmts 1 AB:6 4 wks 1 drops per ear 1x/day Snoring 5 LAT: 6 4 wks 4 ≥50% reductionin drops per snoring ear 1x/day w/both tmts 5 AB: 6 4 wks 4 drops perear 1x/day Allergic Rhinitis 5 LAT: 6 4 wks 4 ≥50% reduction in dropsper sneezing, sniffling, ear 1x/day and congestion 5 AB: 6 4 wks 4w/both tmts drops per ear 1x/day Chronic Sinusitis 5 LAT: 6 4 wks 4 ≥50%reduction in drops per mucous discharge, ear 1x/day sneezing, and 5 AB:6 4 wks 4 congestion drops per w/both tmts ear 1x/day Chronic Nasal 5LAT: 6 4 wks 4 ≥50% reduction in Congestion drops per airway obstructionear 1x/day w/both tmts 5 AB: 6 4 wks 4 drops per ear 1x/day Allergic 5LAT: 6 4 wks 5 ≥50% reduction in Conjunctivitis drops per burning,redness, and ear 1x/day tearing 5 AB: 6 4 wks 5 w/both tmts drops perear 1x/day Sneezing 5 LAT: 6 4 wks 5 ≥70% reduction in drops persneezing ear 1x/day w/both tmts 5 AB: 6 4 wks 5 drops per ear 1x/dayHiccups (acute and 5 LAT: 6 4 wks 4 ≥70% reduction in chronic) drops perhiccups ear 1x/day w/both tmts 5 AB: 6 4 wks 4 drops per ear 1x/dayRhinitis 5 LAT: 6 4 wks 4 reduction of drops per congestion, runny ear1x/day nose, and sneezing 5 AB: 6 4 wks 4 w/both tmts drops per ear1x/day Tinnitus 5 LAT: 6 4 wks 1 Noticeable 50% drops per reduction inringing ear 1x/day in ear Dysphagia 5 LAT: 6 4 wks 4 50% easier to dropsper swallow ear 1x/day w/both tmts 3 AB: 6 4 wks 2 drops per ear 1x/dayEar Pain (acute and 5 LAT: 6 4 wks 2 70% less ear pain chronic) dropsper w/both tmts ear 1x/day 8 AB: 6 4 wks 5 drops per ear 1x/day NeckPain 3 LAT: 6 4 wks 2 50% less neck pain drops per w/both tmts ear1x/day 3 AB: 6 4 wks 2 drops per ear 1x/day Dry Eye Syndrome 4 LAT: 6 4wks 3 less redness, matting, drops per and dry eyes ear 1x/day w/bothtmts 2 AB: 6 4 wks 1 drops per ear 1x/day Trigeminal 5 LAT: 6 4 wks 450% less facial pain Neuralgia Pain drops per w/both tmts ear 1x/day 3AB: 6 4 wks 2 drops per ear 1x/day Temporomandibular 5 LAT: 6 4 wks 4≥70% reduction of Joint Pain drops per jaw pain ear 1x/day w/both tmts 3AB: 6 4 wks 2 drops per ear 1x/day

TABLE 4 Clinical Experiments with Gastroenterology/Urology (GU)-relatedafflictions Tmt # of Subjects Protocol Exhibiting % of Subjects # of (1mL ≈ Clinical Exhibiting Clinical GU-related Subjects 15-20 TmtImprovement Improvement in affliction Treated drops) Time in SymptomsSymptoms Overactive 5 LAT: 6 4 wks 5 ≥50% reduction of bladder drops perurination frequency ear 1x/day and urgency, and 3 AB: 6 4 wks 2 nocturiadrops per decreased bladder ear 1x/day spasm w/both tmts Interstitial 2LAT: 6 4 wks 2 ≥50% reduction of Cystitis drops per burning, dysuria,and ear 1x/day pressure 1 AB: 6 4 wks 1 ≥90% reduction in drops per painduring urination ear 1x/day w/both tmts Dysmenorrhea 5 LAT: 6 4 wks 5≥50% reduction of drops per menorrhea pain ear 1x/day w/both tmts 3 AB:6 4 wks 2 drops per ear 1x/day Pelvic Pain 5 LAT: 6 4 wks 5 ≥50%reduction of drops per pelvic pain from ear 1x/day infection, surgery or3 AB: 6 4 wks 2 ovaries, and fibroids drops per w/both tmts ear 1x/dayChronic 1 LAT: 6 4 wks 1 ≥50% reduction in Prostatitis drops per painand pressure Pain ear 1x/day w/both tmts 1 AB: 6 4 wks 1 drops per ear1x/day eclampsia LAT: 6 4 wks expect to see drops per Reduction of rapidear 1x/day weight gain from body AB: 6 4 wks fluids, abdominal pain,drops per hpt, and urine output, ear 1x/day nausea and vomiting, blurredvision w/both tmts Preeclampsia LAT: 6 4 wks expect to see drops perReduction of HPT, ear 1x/day headaches, Nausea AB: 6 4 wks and Vomitingdrops per w/both tmts ear 1x/day HELLP LAT: 6 4 wks expect to seeSyndrome drops per Reduction of HPT, ear 1x/day abdominal pain, AB: 6 4wks headaches, nausea and drops per vomiting, shoulder ear 1x/day pain,and swelling w/both tmts Cystitis Pain 5 LAT: 6 4 wks 5 ≥50% reductionin drops per pain ear 1x/day w/both tmts 1 AB: 6 4 wks 1 drops per ear1x/day Kidney Pain 2 LAT: 6 4 wks 2 ≥50% reduction in (from stone, dropsper pain from stone, infection, ear 1x/day infection, tumor, etc tumor)1 AB: 6 4 wks 1 w/both tmts drops per ear 1x/day Enuresis 5 LAT: 6 4 wks5 ≥50% reduction in bed drops per wetting ear 1x/day w/both tmts 3 AB: 64 wks 3 drops per ear 1x/day Dysuria 5 LAT: 6 4 wks 5 ≥50% reduction indrops per pain with urination ear 1x/day (e.g., bladder 2 AB: 6 4 wks 2infection) drops per w/both tmts ear 1x/day Dyspareunia 5 LAT: 6 4 wks 4≥70% reduction in drops per painful intercourse ear 1x/day w/both tmts 3AB: 6 4 wks 2 drops per ear 1x/day Encopresis 1 LAT: 6 4 wks 1 ≥75%reduction in drops per episodes of defecation ear 1x/day in clothing inchildren 2 AB: 6 4 wks 2 older than 3 drops per w/both tmts ear 1x/dayMenorrhagia 5 LAT: 6 4 wks 5 ≥75% reduction in (Heavy Flow drops perflow and all had Periods) ear 1x/day decreased number of 3 AB: 6 4 wks 2days drops per (i.e. 2 days) ear 1x/day w/both tmts Frequent 5 LAT: 6 4wks 5 ≥50% reduction in Urination drops per frequency ear 1x/day (dailyand nightly) 3 AB: 6 4 wks 2 w/both tmts drops per ear 1x/dayMenometrorrhagia 4 LAT: 6 4 wks 4 ≥50% reduction in (Prolonged drops perbleeding from cycle Vaginal ear 1x/day period reduced by at Bleeding) 2AB: 6 4 wks 2 least 2 days drops per w/both treatments ear 1x/day

TABLE 5 Clinical Experiments with Gastrointestinal (GI)-relatedafflictions # of Subjects Tmt Exhibiting % of Subjects # of ProtocolClinical Exhibiting Clinical GI-related Subjects (1 mL ≈ 15- TmtImprovement Improvement in affliction Treated 20 drops) Time in SymptomsSymptoms Irritable Bowel 5 LAT: 6 4 wks 5 ≥50% reduction in Syndromedrops per diarrhea and constipation ear 1x/day 3 AB: 6 4 wks 2 —w/bothtreatments drops per ear 1x/day Ulcerative 2 LAT: 6 4 wks 2 ≥50%reduction in pain, Colitis drops per diarrhea, cramping, ear 1x/dayrectal bleeding, and joint pain 1 AB: 6 4 wks 1 —w/both treatments dropsper ear 1x/day Gastroesophageal 5 LAT: 6 4 wks 5 ≥50% reduction inReflux (Acid drops per bloating, gas, heartburn, Reflux) ear 1x/day andpain 5 AB: 6 4 wks 2 —w/both treatments drops per ear 1x/day GastritisPain 5 LAT: 6 4 wks 5 ≥50% reduction in drops per stomach pain and ear1x/day burning 3 AB: 6 4 wks 2 —w/both treatments drops per ear 1 x/dayGastroenteritis 1 LAT: 6 4 wks 1 ≥50% reduction in drops per nausea,vomiting, ear 1x/day diarrhea, abdominal cramping 1 AB: 6 4 wks 1 ≥75%reduction in drops per nausea and vomiting, ear 1 x/day abdominalcramping, diarrhea Hyperemesis 1 LAT: 6 4 wks 1 25% reduction Gravidarumdrops per in nausea ear 1 x/day and vomiting Pediatric Colic 1 LAT: 6 4wks 1 ≥50% reduction in drops per cramp pain and bowel ear 1x/daymovements 1 AB: 6 4 wks 1 —w/both treatments drops per ear 1 x/dayAppetite 5 LAT: 6 4 wks 4 at least 4 lb. weight Suppression drops perloss per month less ear 1 x/day snacking decreased meal size intake 3AB: 6 4 wks 2 —w/both treatments drops per ear 1x/day Gall Bladder 2LAT: 6 4 wks 2 ≥50% reduction in pain Pain drops per ear 1x/day 2 AB: 64 wks 2 —w/both treatments drops per ear 1x/day Chronic 5 LAT: 6 4 wks 4At least 50% more constipation drops per bowel movements ear 1x/day perweek 3 AB: 6 4 wks 2 —w/both treatments drops per ear 1x/day Chronicdiarrhea 5 LAT 6 4 wks 4 At least 50% less drops per episodes ofdiarrhea ear 1x/day 3 AB: 6 4 wks 2 —w/both treatments drops per ear1x/day Pancreatitis pain 4 LAT: 6 4 wks 3 ≥50% reduction in drops perabdominal pain ear 1x/day 2 AB: 6 4 wks 1 —w/both treatments drops perear 1x/day

TABLE 6 Clinical Experiments with Cardiac-related afflictions # ofSubjects Exhibiting Tmt Clinical % of Subjects Protocol Improve-Exhibiting Cardiac- # of (1 mL ≈ ment Clinical related Subjects 15-20Tmt in Improvement affliction Treated drops) Time Symptoms in SymptomsParoxysmal, 1 LAT: 6 4 wks 1 50% less atrial lone, vagal drops perfibrillation mediated ear atrial 1x/day fibrillation 2 LAT: 6 4 wks 270% less Orthostatic drops per episodes (Neurogenic) ear of drops ofHypotension 1x/day blood pressure 1 AB: 6 4 wks 1 —w/both dropstreatments per ear 1x/day Reflex 1 LAT: 6 4 wks 1 decreased Asystolicdrops per seizures Syncope ear 1x/day and spasms Postural 2 LAT: 6 4 wks2 No drop in Orthostatic drops per blood pressure Tachycardia ear Noincrease Syndrome 1x/day in heart rate (POTS) 2 AB: 6 4 wks 2 —w/bothdrops treatments per ear 1x/day Vasovagal 5 LAT: 6 4 wks 5 100%reduction Reflex drops per in vasovagal ear 1x/day reflex syncope 5 AB:6 4 wks 5 —w/both drops treatments per ear 1x/day Cough from 1 LAT: 6 4wks 1 decreased cardiac drops per coughing surgery ear 1x/day incidentsPremature 3 LAT: 6 4 wks 3 normalization Atrial drops per of heartbeatsContractions ear 1x/day Supra- 3 LAT: 6 4 wks 3 Decreased ventriculardrops per palpitations, Tachycardia ear 1x/day chest discomfort, andlightheadedness

TABLE 8 Clinical Experiments with Pulmonary-related afflictions Tmt # ofSubjects % of Subjects Protocol Exhibiting Exhibiting Pulmonary- # of (1mL ≈ Clinical Clinical related Subjects 15-20 Tmt ImprovementImprovement affliction Treated drops) Time in Symptoms in SymptomsAsthma 100 LAT: 6 4 wks 100 Reduced cough drops per Reduce inhaler earusage 1x/day 100 AB: 6 4 wks 100 —w/both drops per treatments ear 1x/dayCOPD 2 LAT: 6 4 wks 2 Reduced cough drops per Reduced ear chest pressure1x/day Decreased shortness of breath 2 AB: 6 4 wks 2 —w/both drops pertreatments ear 1x/day Congestive LAT: 6 4 wks Expect to see a Heartdrops per decrease in Failure ear coughing and (CHF) 1x/day wheezing;AB: 6 4 wks decreased drops per water retention; ear and decreased1x/day dizziness and fatigue Chronic 5 LAT: 6 4 wks 5 DecreasedBronchitis drops per coughing symptoms ear and reduction 1x/day ofmucous Less chest tightness 5 AB: 6 4 wks 5 —w/both drops per treatmentsear 1x/day Asthmatic 5 LAT: 6 4 wks 5 Decreased Bronchitis drops percoughing and symptoms ear reduction 1x/day of mucous 1 AB: 6 4 wks 1—w/both drops per treatments ear 1x/day Cystic 1 LAT: 6 4 wks 1 Betterbreathing Fibrosis drops per capability ear 1x/day

TABLE 7 Clinical Experiments with Metabolism-related afflictions Tmt #of Subjects % of Subjects Metab- Protocol Exhibiting Exhibiting olism- #of (1 mL ≈ Clinical Clinical related Subjects 15-20 Tmt ImprovementImprovement in affliction Treated drops) Time in Symptoms SymptomsHyper- 5 LAT: 6 4 wks 4 20% reduction in tension drops per systolicpressure ear 10% reduction in 1x/day diastolic pressure 5 AB: 6 4 wks 4—w/both drops per treatments ear 1x/day Diabetes 5 LAT: 6 4 wks 4 20%reduction drops per in a.m. fasting, ear less hunger 1x/day 5 AB: 6 4wks 4 —w/both drops per treatments ear 1x/day Hyper- 5 LAT: 6 4 wks 4reduction in serum glycemia drops per glucose levels to ear desiredtarget 1x/day Hyper- 5 LAT: 6 4 wks 3 reduction in serum choles- dropsper cholesterol levels teremia ear to desired target 1x/day

The diseases that are treatable by the disclosed methodology arenumerous. Any disease that is associated with an organ or bodily tissuethat is innervated by the particular nerve could potentially be treatedby the present methods. Particular mention of the following diseasestreatable by the present methods is made: asthma, neurogenic cough,globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease,and obesity. The present methods are also suitable for treatingpost-tonsillectomy or post-adenoidectomy pharyngeal pain, ororopharyngeal pain.

In yet other embodiments, the diseases treatable by the disclosedmethodology include, but are not limited to: cardiac diseases,paroxysmal (lone) (vagal) atrial fibrillation, reflex systolic syncope,postural orthostatic tachycardia syndrome (POTS), excessive gag reflex,esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain,esophageal neuralgia, gastritis, dyspepsia, gall bladder disease,colecistitis pain, abdominal pain, esophageal motility disorder oresophageal dysmotility, spastic colon, pancreatic pain or spasms,pediatric colic, rectal spasms and pain, bladder spasm (overactivebladder), interstitial cystitis, dysmenorrhea, premature labor, pelvicpain, chronic pelvic pain, chronic prostatitis pain, eclampsia,preeclampsia, HELLP syndrome, cystitis pain, irritable bowel syndrome,Cohn's disease, ulcerative colitis, reflux disease, gastritis,gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic,hepato-renal syndrome, appetite suppression, gall bladder pain,inflammation of the esophagus, inflammation of the stomach, inflammationof the colon, kidney pain (from stone, infection, or tumor), enuresis,dysuria, dyspareunia, encopresis, heavy flow periods, frequenturination, prolonged vaginal bleeding, inhibit erections, prevention ofpremature ejaculation, inhibit excessive sweating, ureteral spasms,menstrual cramps, uterine spasms, ovarian pain and spasms, fallopiantube pain and spasms, pediatric asthma, adult asthma, chronicobstructive pulmonary disease (COPD), bronchial mucus, acute bronchitis,asthmatic bronchitis, chronic bronchitis, bronchospasm, cystic fibrosis,inflammation of the lung, emphysema, pleuritic chest pain, intercostalmuscle pain, nerve pain, bronchospasm secondary to intubation andextubation, angina pectoris, cardiac vagal blockage, vasovagal reflexblockage, bradycardia, hypotension, orthostatic hypotension,hypertension, diabetes, shock, septic shock, reduction of blood sugar,inflammation of the pancreas, syncope secondary to vagal or cardiacreasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin,neuralgia, laryngospasm, acute laryngitis, laryngeal pain, chroniclaryngitis, post extubation and intubation laryngospasms, palatalmyoclonus, post-tonsillectomy pain, snoring, allergic rhinitis,vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis,chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups,rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome,fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panicattacks, post-traumatic stress disorder, Tourette's syndrome, focaldystonia, tic doloreaux, bulimia, anxiety, depression, restless legsyndrome, dysautonomia, familial intentional tremor, migraines, autismspectrum, anxiety headaches, insomnia, multiple sclerosis, modulation ofthe reticular activating system, peripheral neuropathy, apraxia, neckand shoulder pain, and Parkinson's disease.

In particular, improvement was reported in over half of the patientstreated in accordance with the above methods, where there were minimumof 5 patients treated for symptoms or conditions associated with thefollowing diseases or disorders, vasovagal reflex blockage, chronicbronchitis, asthmatic bronchitis, hypotension, hypertension, diabetes,bladder spasm, dysmenorrhea, pelvic pain, cystitis pain, enuresis,dysuria, dyspareunia, heavy menstrual flow periods, frequent urination,spasmodic dysphonia, snoring, allergic rhinitis, vasomotor rhinitis,chronic sinusitis, chronic nasal congestion, allergic conjunctivitis,sneezing, hiccups, rhinitis, dysphagia, irritable bowel syndrome,gastritis, appetite suppression, chronic fatigue syndrome, fibromyalgia,anxiety, depression, restless leg syndrome, familial intentional tremor,migraines, autism spectrum, anxiety headaches, insomnia, sleepdisorders, apraxia, and neck and shoulder pain. Similar positive results(i.e., positive results reported for all or more than half of allpatients treated) also were seen with the other listed diseases orclosely-related diseases.

While the methods for treating various diseases associated with thevagus and other cranial nerves have been described in the application inconnection with various embodiments, the scope of the methods is notintended to be limited to the particular embodiments so disclosed. Buton the contrary, the methods are intended to cover such alternatives,modifications, and equivalents, as may be included within the scope andspirit of the below claims.

Example 11—Treatment of Diseases

Embodiments of the invention comprise modulation of the general somaticafferent nerves and general visceral afferent nerves, by administeringone or more anesthetic(s), (for example, either alone or in combination,such as Lidocaine or Bupivicaine) in solution with a carrier, such as anexcipient, Polyetheylene Glycol. “Modulation” can refer to the abilityof the compounds and/or compositions described herein to either enhance(i.e., stimulate) or inhibit (i.e., block) the activity of nerves, suchas one or more of cranial nerves, general somatic afferent fibers,general visceral afferent fibers, and the like. For example, the generalvisceral afferent fibers (GVA) conduct sensory impulses (usually pain orreflex sensations) from the internal organs, glands, and blood vesselsto the central nervous system. They are considered to be part of theautonomic nervous system. Embodiments described herein can modulate thegeneral visceral afferent fibers, such as those of the vagus nerve.

The invention further provides for the modulation of the sympathetic andparasympathetic nervous systems, by auricular anesthesia to auricularbranches of the vagus, glossopharyngeal, and facial nerves and theirconnections to the sympathetic ganglion. Anesthesia to the ganglion ofcranial nerves 5, 7, 9 and 10, and the sympathetic nervous systemresults in their respective downward modulation. Overactive sympatheticand parasympathetic nervous systems are clearly implicated in thedevelopment and metastasis of certain types of malignancies, namelyProstate Cancer, Ovarian Cancer, Breast Cancer, and LymphoblasticLeukemia.

Embodiments of the invention comprise treating, preventing, or providingsymptomatic relief of infection-related afflictions. The term“infection-related affliction” can refer to an affliction that comprisesor results from the invasion of a subject's body and/or body tissue bymicroorganisms, their multiplication, and the reaction of the subject'simmune system to the microorganism. Non-limiting examples of infectionsas described herein comprise those of the Herpes Simplex virus (HSV type1 or HSV type 2, for example) and the Varicella-zoster virus (VZV).

Embodiments of the invention comprise treating, preventing, or providingsymptomatic relief of skin-related afflictions. The term “skin-relatedaffliction” can refer to an affliction that comprises or affects theintegumentary system which covers the entire surface of the body and iscomposed of skin, hair, nails, and related muscles and glands.Skin-related afflictions can be temporary or permanent. Non-limitingexamples of skin conditions comprise facial flushing (such as HotFlashes), facial blushing, Alopecia Areata, Atopic Dematitis, ChronicEczema, Acne Vulgaris, Oily Skin, Rosacea, or Morgellons Disease.

Embodiments of the invention comprise treating, preventing, or providingsymptomatic relief of cell proliferation-related afflictions. The term“cell proliferation-related affliction” can refer to an affliction thatcomprises or results from the uncontrollable proliferation of cellswithin a subject's tissues and the reaction of the subject's immunesystem to the cell proliferation and/or growth. Non-limiting examples ofcell-proliferation related conditions comprise cancers (e.g., solidtumors and liquid cancers) and mastocytosis.

Embodiments of the invention comprise treating, preventing, or providingsymptomatic relief of blood flow-related afflictions. The term “bloodflow-related affliction” can refer to an affliction that ischaracterized by alterations in the flow of blood through a subject'svascular system and/or alters the flow of blood through a subject'svascular system. For example, a blood flow-related affliction can resultin an increase in the flow of blood through a subject's vascular system.As another example, a blood flow-related affliction can result in adecrease in the flow of blood through a subject's vascular system.Non-limiting examples of blood flow-related afflictions compriseerectile dysfunction, sickle cell disease, or wound healing.

A test of an embodiment of the present method was conducted to evaluatethe efficacy of the method for treating patients suffering from aninfection-related affliction, cardiac-related afflictions,metabolism-related afflictions, gastroenterology/urology (GU)-relatedafflictions, skin-related afflictions, neurology-psychiatry-related,cell proliferation-related afflictions, and blood flow-relatedafflictions. Subjects suffering from such afflictions were instructed toutilize drops of a pharmaceutical composition comprising lidocaine (4%)and bupivacaine (2%), in one or both ears, at least one time per day(for example, either in the morning or at night), for a period of timeas needed (Tmt Time).

TABLE 9 Clinical Experiments with Infection-related afflictions # ofSubjects Exhibiting Clinical Infection- # of Tmt Improve- relatedSubjects Protocol Tmt ment in Clinical afflictions Treated (XYZ) TimeSymptoms Improvement Herpes 1 6 drops per at least 1 Prevent the Simplexear 1x/day 2 emergence of 1 weeks herpes cold sores 1 4% 1 Shorten thelidocaine; course of herpes cold sores 1 2% 1 Reduction in Bupivacainepain of herpes cold sores Herpes 6 drops per at least Prevent theSimplex ear 1x/day 2 emergence of 2 weeks herpes cold sores 4% Shortenthe lidocaine; course of herpes cold sores 2% Reduction in Bupivacainepain of herpes cold sores Varicella 1 6 drops per at least 1 Prevent theZoster ear 1x/day 2 emergence of weeks Varicella infection 1 4% 1Shorten the lidocaine; course of Bupivacaine Varicella infection 1 2% 1Reduction in pain of Varicella infection

TABLE 10 Clinical Experiments with Cardiac-related afflictions # ofSubjects Exhibiting Cardiac- # of Tmt Clinical related Subjects ProtocolTmt Improvement Clinical afflictions Treated (XYZ) Time in SymptomsImprovement premature 10 6 drops per at least 9 Prevent the atrial ear1x/day 2 weeks development contraction 4% of affliction and atriallidocaine; tachycardia 2% Bupivacaine

TABLE 11 Clinical Experiments with Metabolism-related afflictions # ofSubjects Metab- Exhibiting olism- # of Tmt Clinical Clinical relatedSubjects Protocol Tmt Improvement Improve- affliction Treated (XYZ) Timein Symptoms ment Insulin 10 6 drops per at least 9 Resistance ear 1x/day2 weeks 4% lidocaine; 2% Bupivacaine

TABLE 12 Clinical Experiment with Gastroenterology/ Urology (GU)-relatedafflictions # of Subjects Exhibiting Gastro- Clinical enterology/Improve- Urology # of Tmt ment Clinical (GU)-related Subjects ProtocolTmt in Improve- afflictions Treated (XYZ) Time Symptoms ment ChronicRenal 3 6 drops per at least 2 3 Increased Failure ear 1x/day weeksblood flow 4% lidocaine; 2% Bupivacaine

TABLE 13 Clinical Experiment with Skin-related afflictions # of SubjectsExhibiting Skin- # of Tmt Clinical related Subjects Protocol TmtImprovement Clinical affliction Treated (XYZ) Time in SymptomsImprovement facial 9 6 drops per at least 10 flushing ear 1x/day 2 weeks(Hot 4% Flashes) lidocaine; 2% Bupivacaine facial 9 6 drops per at least10 blushing ear 1x/day 2 weeks 4% lidocaine; 2% Bupivacaine Alopecia 4 6drops per at least 4 Areata ear 1x/day 2 weeks 4% lidocaine; 2%Bupivacaine Atopic 2 6 drops per at least 2 Dematitis ear 1x/day 2 weeks4% lidocaine; 2% Bupivacaine Chronic 2 6 drops per at least 2 Eczema ear1x/day 2 weeks 4% lidocaine; 2% Bupivacaine Acne 3 6 drops per at least3 Vulgaris ear 1x/day 2 weeks 4% lidocaine; 2% Bupivacaine Oily Skin 3 6drops per at least 3 ear 1x/day 2 weeks 4% lidocaine; 2% BupivacaineRosacea 2 6 drops per at least 2 ear 1x/day 2 weeks 4% lidocaine; 2%Bupivacaine Morgellons 6 drops per at least Disease ear 1x/day 2 weeks4% lidocaine; 2% Bupivacaine

TABLE 14 Clinical Experimentwith Neuropology- Psychiatry-relatedaffliction # of Subjects Neurology- Exhibiting Psychiatry- # of TmtClinical Clinical related Subjects Protocol Tmt Improvement Improve-affliction Treated (XYZ) Time in Symptoms ment Reflex 20  6 drops per atleast 20  Sympathetic ear 1x/day 2 weeks Dystrophy 4% lidocaine; 2%Bupivacaine Sensory 1 6 drops per at least 1 Processing ear 1x/day 2weeks Disorder 4% lidocaine; 2% Bupivacaine Decreased 2 6 drops per atleast 1 Libido ear 1x/day 2 weeks 4% lidocaine; 2% Bupivacaine

TABLE 15 Clinical Experiment with Cell Proliferation-related afflictions# of Subjects Cell Exhibiting Prolif- Clinical eration- # of TmtImprove- related Subjects Protocol Tmt ment in Clinical afflictionsTreated (XYZ) Time Symptoms Improvement Cancer 3 6 drops at least 3Modulation of perear 2 weeks theSympathetic 1x/day Nervous 4% System andthe lidocaine; prevention and 2% spread of Bupiva- prostate cancer,caine lymphoblastic leukemia, ovarian cancer, breast cancer Preventionof side effects to chemotherapy (Side effects such as pain, fatigue,anxiety, and sympathetic nervous system over- stimulation) Masto- 1 6drops at least 1 cytosis per ear 2 weeks 1x/day 4% lidocaine; 2% Bupiva-caine

TABLE 16 Clinical Experiment with Blood Flow-related afflictions # ofSubjects Exhibiting Blood Clinical Flow- # of Tmt Improve- Clinicalrelated Subjects Protocol Tmt ment in Improve- afflictions Treated (XYZ)Time Symptoms ment Erectile 1 6 drops per at least 1 Dys- ear 1x/day 2weeks function 4% lidocaine; 2% Bupivacaine Open 1 6 drops per at least1 Increase in Wound ear 1x/day 2 weeks peripheral Healing 4% blood flowlidocaine; 2% Bupivacaine Sickle Cell 1 6 drops per at least 1 Diseaseear 1x/day 2 weeks 4% lidocaine; 2% Bupivacaine

Example 12—Treatment of Pain

Embodiments of the invention further comprise treating pain, such aspain that results from a variety of diseases disclosed herein, byperforming auricular anesthesia that indirectly anesthetizes paraspinaland paravertebral ganglion. Those respective ganglion receive generalvisceral afferent signals that are thus modulated. Those modulatedsignals travel from the paraspinal and paravertebral ganglion to thedorsal root ganglion, then to the dorsal grey horn of the spinal cord,where they meet with general somatic afferent signals. Modulated generalvisceral afferent signals modulate the general somatic afferent signalsby this invention, thus modulates pain in both nervous system pathways.

Embodiments of the invention comprise methods of blocking pain from avariety of diseases that comprises performing auricular anesthesia ofthe ear canal and concha, resulting in anesthesia to branches ofcervical nerves 2 and 3 (C2, C3) and cranial nerves 5, 7, 9, and 10. Thetenth cranial nerve, or Vagus Nerve, has direct attachments to theeleventh (11) and twelfth (12) cranial nerves and the sympatheticganglion.

As is known in the art, pain is typically treated by administering ananesthetic or analgesic directly to the site of the pain. For example,U.S. Pat. No. 6,093,417 (Petrus) teaches administration of a topical earcomposition comprising a penetration enhancer directly to the ear itselffor the purpose of reducing inflammation of the inner ear and providingpain relief of the inner ear. However, as described herein, theinvention provided for a method for ameliorating pain in a subjectcomprising administering to the ear canal of a subject a pain relievingcomposition so as to ameliorate pain at a distal site (i.e, non-earpain, away from the site of composition administration).

A test of an embodiment of the method described herein was conducted toevaluate the efficacy of the method for treating patients suffering frompain. Subjects suffering from pain were instructed to utilize drops of apharmaceutical composition comprising antipyrine (≈54.0 mg) andbenzocaine (≈14.0 mg) (treatment protocol, “AB” Tmt Protocol) or dropsof a pharmaceutical composition comprising lidocaine (≈40.0 mg) andtetracaine (≈5.0 mg) (treatment protocol, “LAT” Tmt Protocol), in one orboth ears, at least one time per day (for example, either in the morningor at night), for a period of time as needed (Tmt Time). The LAT oticsolution used in the tests comprises 4% Lidocaine, 0.5% Tetracaine,1/100,000 Epinephrine, and Anhydrous Glycerine. The AB otic solutionused in the tests comprises 5.4% Antipyrine, 1.4% Benzocaine,Oxyquinoline Sulfate, and Anhydrous Glycerine.

TABLE 17 Clinical Experiment with Pain-related afflictions # of SubjectsExhibiting # of Tmt Clinical Pain-related Subjects Protocol TmtImprovement Clinical afflictions Treated (XYZ) Time in SymptomsImprovement Post-Tonsillectomy 500 6 drops For 10 495 Pharyngeal or perear days post Oropharyngeal Pain 3 times operation per day Post- 200 6drops For 7 200 Adenoidectomy per ear days post Pharyngeal or 2 timesoperation Oropharyngeal Pain per day Laryngeal Pain 2 6 drops As 2 perear needed once a day Migraine Pain 5 LAT: 6 4 wks 4 ≥70% reduction indrops migraine headaches per per ear month (frequency, 1x/day duration,and intensity) 3 AB: 6 4 wks 2 —w/both tmts drops per ear 1x/day AnxietyHeadaches 5 LAT: 6 4 wks 5 ≥75% reduction in drops headaches per monthper ear (frequency, duration, 1x/day and intensity) 5 AB: 6 4 wks 2—w/both tmts drops per ear 1x/day Peripheral 5 LAT: 6 4 wks 4 ≥50%reduction in Neuropathy drops peripheral pain per ear 1x/day 5 AB: 6 4wks 4 —w/both tmts drops per ear 1x/day Neck and 5 LAT: 6 4 wks 5 ≥50%reduction Shoulder drops in pain Pain per ear 1x/day 3 AB: 6 4 wks 2—w/both tmts drops per ear 1x/day General Somatic 4 LAT: 6 4 wks 3 lessneck, back, arm, Afferent Pain— drops leg, shoulder, and Neuromuscularper ear chest pain Pain 1x/day 2 AB: 6 4 wks 1 —w/both tmts drops perear 1x/day General Somatic 4 LAT: 6 4 wks 3 ≥50% reduction in painAfferent drops requiring less pain Pain—Joint per ear medications Pain1x/day (nonspecific) 3 AB: 6 4 wks 2 —w/both tmts drops per ear 1x/dayGeneral Somatic 4 LAT: 6 4 wks 3 reduction in pain Afferent Pain— dropsSciatica pain per ear 1x/day General Somatic 4 LAT: 6 4 wks 3 reductionin pain Afferent Pain— drops Arthritis pain per ear 1x/day GeneralSomatic 4 LAT: 6 4 wks 3 reduction in pain Afferent Pain— drops ShinglesPain per ear 1x/day General Somatic 3 LAT: 6 4 wks 3 ≥70% reduction inAfferent Pain— drops peripheral pain signals Reflex Sympathetic per earless electrical, sharp Dystrophy pain 1x/day pain 1 AB: 6 4 wks 1—w/both tmts drops per ear 1x/day General Visceral 5 LAT: 6 4 wks 4 ≥70%reduction in Afferent Pain drops esophageal, stomach, per earintestinal, bladder, and 1x/day pelvic pain 1 AB: 6 4 wks 1 —w/both tmtsdrops per ear 1x/day Post Tonsillectomy 50 LAT: 6 4 wks 50 ≥50%reduction in pain Pain drops Reduction of pain per ear medications1x/day 50 AB: 6 4 wks 50 —w/both tmts drops per ear 1x/day PharyngealPain 50 LAT: 6 4 wks 50 ≥70% reduction in drops throat pain per ear1x/day 50 AB: 6 4 wks 50 —w/both tmts drops per ear 1x/day LaryngealPain 5 LAT: 6 4 wks 5 ≥50% reduction in drops laryngeal pain per ear1x/day 5 AB: 6 4 wks 5 —w/both tmts drops per ear 1x/day Ear Pain (acute5 LAT: 6 4 wks 2 70% less ear pain and chronic) drops per ear 1x/day 8AB: 6 4 wks 5 —w/both tmts drops per ear 1x/day Neck Pain 3 LAT: 6 4 wks2 50% less neck pain drops per ear 1x/day 3 AB: 6 4 wks 2 —w/both tmtsdrops per ear 1x/day Trigeminal 5 LAT: 6 4 wks 4 50% less facial painNeuralgia Pain drops per ear 1x/day 3 AB: 6 4 wks 2 —w/both tmts dropsper ear 1x/day Temporomandibular 5 LAT: 6 4 wks 4 ≥70% reduction ofJoint Pain drops jaw pain per ear 1x/day 3 AB: 6 4 wks 2 —w/both tmtsdrops per ear 1x/day Pelvic Pain 5 LAT: 6 4 wks 5 ≥50% reduction ofdrops pelvic pain from per ear infection, surgery or 1x/day ovaries, andfibroids 3 AB: 6 4 wks 2 —w/both tmts drops per ear 1x/day ChronicProstatitis 1 LAT: 6 4 wks 1 ≥50% reduction in Pain drops pain andpressure per ear 1x/day 1 AB: 6 4 wks 1 —w/both tmts drops per ear1x/day Cystitis Pain 5 LAT: 6 4 wks 5 ≥50% reduction drops in pain perear 1x/day 1 AB: 6 4 wks 1 —w/both tmts drops per ear 1x/day Kidney Pain(from 2 LAT: 6 4 wks 2 ≥50% reduction in pain stone, infection, dropsfrom stone, infection, tumor) per ear tumor, etc 1x/day 1 AB:6 4 wks 1—w/both tmts drops per ear 1x/day Gastritis Pain 5 LAT: 6 4 wks 5 ≥50%reduction in drops stomach pain and per ear burning 1x/day 3 AB: 6 4 wks2 —w/both treatments drops per ear 1x/day Gall Bladder Pain 2 LAT: 6 4wks 2 ≥50% reduction drops in pain per ear 1x/day 2 AB: 6 4 wks 2—w/both treatments drops per ear 1x/day Pancreatitis pain 4 LAT: 6 4 wks3 ≥50% reduction in drops abdominal pain per ear 1x/day 2 AB: 6 4 wks 1—w/both treatments drops per ear 1x/day

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific substances and procedures described herein. Such equivalentsare considered to be within the scope of this invention, and are coveredby the following claims.

What is claimed is:
 1. A method for ameliorating pain in a subject, themethod comprising administering to an ear canal of a subject afflictedwith a distal pain an effective amount of a pharmaceutical compositioncomprising at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.
 2. The methodaccording to claim 1, wherein the anesthetic comprises benzocaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine,piperocaine, propoxycaine, procaine, novocaine, proparacaine,tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine,etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine,prilocaine, ropivacaine, farmocaine, trimecaine, or a combination of theanesthetics listed herein.
 3. The method of claim 1, wherein thecomposition further comprises at least one analgesic comprising apyrazolone derivative.
 4. The method of claim 3, wherein the pyrazolonederivative is selected from the group consisting of ampyrone, dipyrone,antipyrine, aminopyrine, and propyphenazone.
 5. The method of claim 1,wherein said pharmaceutical composition is administered in aconcentration sufficient to physiologically alter the activity of thesubject's particular cranial nerve compared to the physiologicalactivity of that particular cranial nerve in a subject not administeredthe pharmaceutical composition.
 6. The method according to claim 5,wherein the particular cranial nerve is the trigeminal nerve, the facialnerve, the glossopharyngeal nerve, the accessory nerve, the hypoglossalnerve, the vagus nerve, or a combination thereof.
 7. The methodaccording to claim 1, wherein the subject does not have an earinfection, ear pain, or a combination thereof.
 8. The method accordingto claim 1, wherein the pharmaceutical composition further comprises oneor more of an antibiotic, a vasoconstrictor, glycerin, epinephrine, oracetic acid.
 9. The method according to claim 1, wherein the amount ofanesthetic does not exceed 252 mg/day.
 10. The method of claim 3,wherein the amount of analgesic administered does not exceed 972 mg/day.11. The method of claim 1, wherein the pain comprises post-tonsillectomypharyngeal or oropharyngeal pain, post-adenoidectomy pharyngeal ororopharyngeal pain, laryngeal pain, migraine pain, anxiety headaches,peripheral neuropathy, neck and shoulder pain, general somatic afferentpain, neuromuscular pain, joint pain, sciatica pain, arthritis pain,shingles pain, reflex sympathetic dystrophy pain, general visceralafferent pain, post tonsillectomy pain, pharyngeal pain, laryngeal pain,neck pain, trigeminal neuralgia pain, temporomandibular joint pain,pelvic pain, chronic prostatitis pain, cystitis pain, kidney pain,gastritis pain, gall bladder pain, and pancreatitis pain.
 12. A methodfor treating a subject suffering from an affliction associated with aparticular cranial nerve, the method comprising administering to an earcanal of a subject an effective amount of a pharmaceutical compositioncomprising at least one anesthetic comprising Formula I:

wherein R₁ comprises:

wherein R₂ comprises H, CH₃, Cl, or

wherein R₃ comprises H or NH₂; wherein R₄ comprises H, NH₂, CH₃,

wherein R₅ comprises H; and wherein R₆ comprises H or CH₃.
 13. Themethod of claim 12, wherein the composition further comprises at leastone analgesic comprising a pyrazolone derivative.
 14. The method ofclaim 12, wherein the affliction comprises aneurology-psychiatry-related affliction, ear-nose-throat (ENT)-relatedaffliction, Gastroenterology/Urology (GU)-related affliction,gastrointestinal (GI)-related affliction, cardiac-related affliction,pulmonary-related affliction, metabolic-related affliction,infection-related affliction, skin-related affliction, cellproliferation-related affliction, or blood flow-related affliction. 15.The method of claim 14, wherein the neurology-psychiatry-relatedaffliction is at least one selected from the group consisting of:chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive CompulsiveDisorder, panic attack, Post-Traumatic Stress Disorder, Tourette'sSyndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression,Restless Leg Syndrome, Dysautonomia, Familial Intentional Tremor,Migraine pain, Autism Spectrum Disorder, Anxiety Headache,sleeplessness, Reticular Activating System (RAS) dysregulation, MultipleSclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain,Parkinson's Disease, General Somatic Afferent Pain, General Visceral,Afferent Pain, opiate withdrawal, Dysarthria, ADHD, Nonspecific handtremor, Stuttering, cerebral palsy, Raynaud's Phenomenon, excessivesweating, reflex sympathetic dystrophy, sensory processing disorder, anddecreased libido.
 16. The method of claim 14, wherein theear-nose-throat (ENT)-related affliction is at least one selected fromthe group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain,Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus,Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis,Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups,Rhinitis, Tinnitus, Dysphagia, neck pain, Dry Eye Syndrome, TrigeminalNeuralgia pain, and Temporomandibular Joint Pain.
 17. The method ofclaim 14, wherein the Gastroenterology/Urology (GU)-related afflictionis at least one selected from the group consisting of: bladder spasm,dysmenorrhea, pelvic pain, Premature Labor, interstitial cystitis,Prostatitis, Eclampsia, pre-eclampsia, HELLP Syndrome, cystitis, KidneyPain, enuresis, dysuria, dyspareunia, encopresis, heavy flowmenstruation, frequent urination, Prolonged Vaginal Bleeding, decreasedrenal blood flow, chronic renal failure.
 18. The method of claim 14,wherein the gastrointestinal (GI)-related affliction is at least oneselected from the group consisting of: irritable bowel syndrome (MS),ulcerative colitis, acid reflux, Gastritis, Gastroenteritis, HyperemesisGravidarum, Pediatric Colic, Hepato-Renal Syndrome, AppetiteSuppression, Gall Bladder Pain, Chronic constipation, Chronic diarrhea,and Pancreatitis.
 19. The method of claim 14, wherein thecardiac-related affliction is at least one selected from the groupconsisting of: Paroxysmal (Lone) (Vagal) Atrial Fibrillation,Orthostatic (Neurogenic) Hypotension, Reflex Asystolic Syncope, PosturalOrthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cardiacsurgery derived cough, heart block, Atrial Contractions, Tachycardia,Congestive Heart Failure, premature atrial contraction, and atrialtachycardia.
 20. The method of claim 14, wherein the pulmonary-relatedaffliction is at least one selected from the group consisting of:asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cysticfibrosis, and Bronchospasm.
 21. The method of claim 14, wherein themetabolic-related affliction is at least one selected from the groupconsisting of: hypertension, diabetes, septic shock, neurogenic shock,hyperglycemia, hypercholesteremia, and insulin resistance.
 22. Themethod of claim 14, wherein the infection-related affliction is at leastone selected from the group consisting of: Herpes Simplex 1 infection,Herpes, Simplex 2 infection, and Varicella Zoster infection.
 23. Themethod of claim 14, wherein the skin-related affliction is at least oneselected from the group consisting of: facial flushing, facial blushing,alopecia areata, atopic dermatitis, chronic eczema, acne vulgaris, oilyskin, rosacea, and morgellons disease.
 24. The method of claim 14,wherein the cell proliferation-related affliction is at least oneselected from the group consisting of: cancer and mastocytosis.
 25. Themethod of claim 14, wherein the blood flow-related affliction is atleast one selected from the group consisting of erectile dysfunction,open wound healing, and sickle cell disease.